Method for treating neoplasms by inhalation

ABSTRACT

A formulation, method, and apparatus for treating neoplasms such as cancer by administering a pharmaceutically effective amount of highly toxic composition by inhalation, wherein the composition is a non-encapsulated antineoplastic drug.

This application is a continuation of 09/000,775 filed Dec. 30, 1997which claims the benefit of U.S. Provisional Application No. 60/033,789filed on Dec. 30, 1996.

FIELD OF THE INVENTION

The invention deals with formulations and methods useful for treatingneoplasms, particularly neoplasms of the respiratory tract (e.g. lungcancer and cancers of the head and neck), by pulmonary administration ofhighly toxic or vesicating anticancer drugs. Additionally, several newformulations and methods for treating neoplasms using antineoplasticdrugs that are nonvesicants are also disclosed.

BACKGROUND OF THE INVENTION

Cancer is one of the leading causes of death worldwide. Lung cancer inparticular, is among the top 3 most prevalent cancers and has a verypoor survival rate (about 13% five-year survival rate). Despite theavailability of many cancer drugs it has been difficult and, in the caseof some cancer types, almost impossible to improve cure rates orsurvival. There are many reasons for this lack of success but one reasonis the inability to deliver adequate amounts of the drugs to the tumorwithout causing debilitating and life-threatening toxicities in thepatient. Indeed, most chemotherapeutic drugs used to treat cancer arehighly toxic to both normal and tumor tissues.

It is customary in the treatment of cancer to administer the drugs bythe intravenous route, which exposes the entire body to the drug. Dosesare selected that destroy tumor cells, but these doses also destroynormal cells. As a result, the patient usually experiences severe toxicside effects. For example, severe myelosuppression may result whichcompromises the ability of the patient to resist infection and allowsspread of the tumor. There are other life-threatening effects such ashepatotoxicity, renal toxicity, pulmonary toxicity, cardiotoxicity,neurotoxicity, and gastrointestinal toxicity caused by anticancer drugs.The anticancer drugs also cause other effects such as alopecia,stomatitis, and cystitis that may not be life threatening, but areserious enough to affect a patient's quality of life. Moreover, it isimportant to note that these toxicities are not associated to the sameextent with all anticancer drugs but are all due to systemic delivery ofthe drug.

Although myelosuppression is commonly associated with most anticancerdrugs, because of differences in the mechanisms by which the variousanticancer drugs act or in the ways they are distributed in the body,metabolized and excreted from the body, each drug presents a somewhatdifferent toxicity profile, both quantitatively and qualitatively. Forexample, anthracyclines such as doxorubicin, epirubicin and idarubicinare known to cause severe cardiotoxicity. Doxorubicin, additionally, isknown to cause severe progressive necrosis of tissues when extravasated.Cisplatin therapy is known to cause renal toxicity; vincristine causesneurotoxicity, bleomycin and mitomycin cause pulmonary toxicity,cyclophosphamide causes cystitis; and 5-fluorouracil causes cerebraldisjunction (see Cancer Chemotherapy: Principles and Practice, B AShabner and J. M. Collings, eds. J. B. Lippincott Co., Philadelphia,1990).

The differences in mechanisms of action and pharmacokinetic propertiesdetermine, in part, the efficacy of the various anticancer drugs againstdifferent tumor types, which exhibit various biological behaviors.

Some attempts have been made to deliver anticancer drugs directly to thetumor or to the region of the tumor to minimize exposure of normaltissues to the drug. This regional therapy, for example has been used totreat liver cancer by delivering drugs directly into the hepatic arteryso that the full dose goes to the liver while reducing the amount thatgoes to the rest of the body. For the treatment of urinary bladdercancer, anticancer drugs are instilled directly into the bladder throughthe urethra, allowed to remain in contact with the tumor for a period oftime and then voided. Other examples of regional therapy include thedelivery of anticancer drugs into the peritoneal cavity to treat cancerthat has developed in or metastasized to this location. Other methods oftargeting anticancer drugs involve the attachment of the drugs toantibodies that seek out and deliver the drug directly to the cancercells.

In 1968 Shevchenko, I. T., (Neoplasma 15, 4, 1968) pp.419-426 reportedon the treatment of advanced bronchial cancer using a combination ofinhalation of chemotherapeutic agents, radiotherapy, and oxygeninhalation. The reported chemotherapeutic agents were benzotaph,thiophosphamid, cyclophosphan and endoxan that were applied as anaerosol by means of an inhaler. For 58 treated patients the combinationof three treatments showed tumor disappearance in 8 cases while in 6 thesize of the tumor diminished considerably. The study did not include acontrol group.

In 1970, Sugawa, I. (Ochanoizu Med. J.; Vol. 18; No.3; (1970),pp.103-114, reported on tests using mitomycin-C in the treatment ofmetastatic lung cancer. One of four patients treated reportedly showedsome improvement. Inhalation of mitomycin-C also appeared to reducetumor growth in IV-inoculated tumors in rabbits; results appeared to bemore inconclusive in rats. Tests were conducted to determine the toxiceffects to the respiratory tract following intrabronchial infusions ofseveral drugs. The drugs were given to healthy animals and included:thiotepa (rats), Toyomycin (chromomycin A3) (rats,), endoxan(cyclophosphamide) (rats and rabbits), 5-fluorourcil (rats and rabbits),mitomycin-C (rats, rabbits, and dogs). The results of these tests showedthat: 5-FU and cyclophosphamide resulted in only mild inflammation;thiotepa produced bronchial obstruction; chromomycin A3 and mitomycin-Cproduced the most severe results. Toxic effects of mitomycin-C andchromomycin A3 were studied in rabbits and dogs.

In 1983, Tatsumura et al (Jap. J. Cancer Cln., Vol. 29, pp. 765-770)reported that the anticancer drug, fluorouracil (5-FU, MW=130) waseffective for the treatment of lung cancer in a small group of humanpatients when administered directly to the lung by aerosolization. Theyreferred to this as nebulization chemotherapy. It was also noted byTatsamura et al (1993) (Br. J. Cancer, Vol. 68(6): pp.1146-1149) thatthe 5-FU did not cause toxicity to the lung. This finding was nottotally unexpected because 5-FU has a very low molecular weight and doesnot bind tightly to proteins. Therefore, it passes through the lungrapidly lessening the opportunity to cause local toxicity. Moreover 5-FUis considered to be one of the least toxic anticancer drugs when applieddirectly to tissue. Indeed, 5-FU is used as a topical drug for thetreatment of actinic keratosis for which it is applied liberally, twicedaily, to lesions on the face. This therapy may continue for up to fourweeks. Also, because 5-FU is poorly absorbed from the gastrointestinaltract, there is little concern about the amount of drug that may beinadvertently swallowed and gain access to the blood stream from thegut. It is well known that a large percentage of aerosolized drugintended for the lung is swallowed.

Another report includes the use of β-cytosine arabinoside (Ara-C,cytarabine, MW=243) administered via intratracheal delivery to therespiratory system of rats. Liposome encapsulated and free Ara-C wereinstilled intratracheally to the rats as a bolus. The encapsulated Ara-Cpersisted for a long time in the lung while the free Ara-C which is nothighly protein bound was rapidly cleared from the lung. The free Ara-Crapidly diffused across the lung mucosa and entered the systemiccirculation. The paper suggests that liposome encapsulation of drugs maybe a way to produce local pharmacologic effect within the lung withoutproducing adverse side effects in other tissues. However, bolusadministration results in multifocal concentrated pockets of drug. Seethe articles by H. N. MacCullough et al, JNCI, Vol. 63, No. 3,September, pp.727-731 (1979) and R. L. Juliano et al, J. Ph. & Exp.Ther., Vol. 214, No.2, pp.381-387 (1980).

An additional report includes the use of cisplatin (MW=300) forinhalation chemotherapy in mice that had been implanted with FM3A cells(murine mammary tumor cells) in the air passages. The cisplatin exposedinhalation group were reported to have statistically smaller lung tumorsizes and survived longer than the untreated control group. See A.Kinoshita, “Investigation of Cisplatin Inhalation Chemotherapy Effectson Mice after Air Passage Implantation of FM3A Cells”, J. Jap. Soc.Cancer Ther. 28(4): pp. 705-715 (1993).

In U.S. Pat. No. 5,531,219 to Rosenberg, the patent disclosure suggeststhe use of doxorubicin, 5-FU, vinblastine sulfate, or methotrexate incombination with pulmonary infused liquid fluorocarbons. The patient issuggested to be positioned so that the tumor affected area is at agravitational low point so that liquid perfluorocarbon having relativelylow vapor pressure will pool selectively around the area with the drugthen perfused in the pool of liquid perfluorocarbon. The presentinvention avoids the problems with positioning of the patient andfurther does not require the liquid fluorocarbons used by Rosenberg.

In U.S. Pat. No. 5,439,686 to Desai et al there are disclosedcompositions where a pharmaceutically active agent is enclosed within apolymeric shell for administration to a patient. One of the routes ofadministration listed as possible for the compositions of the inventionis inhalational. Among the listed pharmaceutically active agentspotentially useful in the invention are anticancer agents such aspaclitaxel and doxorubicin. No tests using the inhalational rout ofadministration appear to have been made.

Although several antineoplastic drugs have been administered to animalsand to humans, for treatment of tumors in the lungs and respiratorysystem, the differences in the mechanism of action, and toxicityprofiles among the broad classes of anticancer drugs, and the heretoforeknown characterizations have made it impossible to predict whether aparticular anticancer drug will be efficacious or toxic based uponprevious inhalation results with a different drug of a different type.Further, previous reports used very imprecise means of delivering drugsand were not consistent in delivering measured doses of drugs in anevenly distributed manner to the entire respiratory tract. The presentinvention provides means for predicting and selecting drugs includingthe highly toxic chemotherapeutic compounds, amenable for inhalationtherapy of neoplastic disease and methods for actually distributingspecific measured doses to pre-selected regions of the respiratorytract.

It has now been demonstrated by the applicants that anticancer cytotoxicdrugs of multiple classes such as anthracyclines (doxorubicin),antimicrotubule agents such as the vinca alkaloids (vincristine), andtaxanes such as paclitaxel can be given directly by inhalation withoutcausing severe toxicity to the lung or other body organs. This findingis surprising, because it is well known among those who administercytotoxins such as doxorubicin to patients, that this drug causes severeulceration of the skin and underlying tissues if allowed to be deliveredoutside of a vein. After extravasation the drug continues to affect thetissues to such an extent that amputation of limbs in which theextravasation has occurred has been required. So severe is this toxicitythat the prescribing information for doxorubicin (and some other similarvesicating drugs) in the Physicians Desk Reference contains a “BoxWarning” regarding this danger. The present invention, therefore,provides an effective way to administer chemotherapeutic agents,including highly toxic agents such as doxorubicin, while minimizing themajor side effects described above.

BRIEF DESCRIPTION OF THE INVENTION

Broadly, one embodiment of the invention includes a formulation fortreating a patient for a neoplasm by inhalation comprising: a safe andeffective amount of a vesicant and a pharmaceutically acceptablecarrier, preferably the vesicant does not exhibit substantial pulmonarytoxicity. In one aspect of the embodiment the vesicant is typically amoderate vesicant such as paclitaxel or carboplatin. A description ofsuch a moderate vesicant would include a non-encapsulated anticancerdrug, wherein when 0.2 ml of the drug is injected intradermally to rats,at the clinical concentration for parenteral use in humans: (a) a lesionresults that is at least 20 mm² in area fourteen days after theintradermal injection; and (b) at least 50% of the tested rats have thissize of lesion. Other aspects of this broad embodiment typically includea vesicant that is a severe vesicant such as doxorubicin, vincristine,and vinorelbine. The neoplasm to be treated is typically a pulmonaryneoplasm, a neoplasm of the head and neck, or other systemic neoplasm.The drug may be in the form of a liquid, a powder, a liquid aerosol, ora powdered aerosol. Typically the patient is a mammal such as a domesticanimal or a human. In other aspects the embodiment includes formulationsof drugs such as etoposide and a carrier such as DMA. Typically thesevere vesicant is an anthracycline such as epirubicin, daunorubicin,methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, doxorubicin,or idarubicin; or a vinca alkaloid such as vincristine, vinorelbine,vinorelbine, vindesine, or vinblastine. In other formulations the drugis typically mechlorethamine, mithramycin, dactinomycin, bisantrene, oramsacrine. Typically the formulation may include a taxane such aspaclitaxel, its derivatives and the like. Typical animal and human dosesare provided in the tables and text below.

A further broad embodiment of the invention includes a formulation fortreating a patient having a neoplasm by inhalation comprising: a safeand effective amount of a non-encapsulated antineoplastic drug having amolecular weight above 350, that does not exhibit substantial pulmonarytoxicity; and an effective amount of a pharmaceutically acceptablecarrier. The neoplasm treated with the formulation is typically apulmonary neoplasm, a neoplasm of the head and neck, or a systemicneoplasm. The drug used in the formulation is in the form of a liquid, apowder, a liquid aerosol, or a powdered aerosol. Typically the drug hasa protein binding affinity of 25% or 50% or more. Further the drug cantypically have a higher molecular weights such as above 400, 450, or 500daltons. Typical animal and human doses are provided in the tables andtext below.

In a yet further embodiment of the invention, there is disclosed aformulation for treating a patient for a neoplasm by inhalationcomprising: a safe and effective amount of a taxane in an effectiveamount of vehicle comprising polyethyleneglycol (PEG) and an alcohol.Typically the formulation will also contain an acid, where the acidpresent in amount effective to stabilize the taxane. Typically thealcohol is ethanol, and the acid is an inorganic acid such as HCl, or anorganic acid such as citric acid and the like. In some typicalformulations the taxane is paclitaxel and the formulation contains about8% to 40% polyethyleneglycol, about 90% to 60% alcohol, and about 0.01%to 2% acid. Typical animal and human doses are provided in the table andtext below.

Another embodiment provides for formulations for treating a patient fora neoplasm by inhalation comprising: a safe and effective amount of adrug selected from the group consisting of carmustine, dacarbazine,melphalan, mercaptopurine, mitoxantrone, esorubicin, teniposide,aclacinomycin, plicamycin, streptozocin, and menogaril; and a safe andeffective amount of a pharmaceutically effective carrier, wherein thedrugs do not exhibit substantial pulmonary toxicity.

A yet further embodiment provides for a formulation for treating apatient for a neoplasm by inhalation comprising: a safe and effectiveamount of a drug selected from the group consisting of estramustinephosphate, geldanamycin, bryostatin, suramin, carboxyamido-triazoles;onconase, and SU101 and its active metabolite SU20; and a safe andeffective amount of a pharmaceutically effective carrier, wherein thedrugs do not exhibit substantial pulmonary toxicity.

A still further embodiment provides for a formulation for treating apatient for a neoplasm by inhalation comprising: a safe and effectiveamount of etoposide and an effective amount of a DMA carrier. Typicalanimal and human doses are provided in the tables and text below.

Another embodiment includes a formulation for treating a patient for aneoplasm by inhalation comprising: a safe and effective amount of amicrosuspension of 9-aminocamptothecin in an aqueous carrier. Typicalanima and human doses are provided in the tables and text below.

A further broad embodiment of the invention includes a formulation fortreating a patient having a neoplasm comprising: administering to thepatient by inhalation, (1) an effective amount of a highly toxicantineoplastic drug; and (2) an effective amount of a chemoprotectant,wherein the chemoprotectant reduces or eliminates toxic effects in thepatient that are a result of administering the highly toxicantineoplastic drug. Typically the chemoprotectant reduces or eliminatessystemic toxicity in the patient, and/or reduces or eliminatesrespiratory tract toxicity in the patient. Typically the formulationincludes a chemoprotectant such as dexrazoxane (ICRF-187), mesna(ORG-2766), ethiofos (WR2721), or a mixture thereof. The chemoprotectantmay be administered before, after, or during the administration of theantineoplastic drug. The antineoplastic drug used with thechemoprotectant may be a nonvesicant, moderate vesicant, or a severevesicant. Typical among the drugs with which the chemoprotectant isuseful are bleomycin, doxorubicin, and mitomycin-C.

The invention also typically includes a method for treating a patienthaving a neoplasm comprising: administering to the patient byinhalation, (1) an effective amount of a highly toxic antineoplasticdrug; and (2) an effective amount of a chemoprotectant, wherein thechemoprotectant reduces or eliminates toxic effects in the patient thatare a result of administering the highly toxic antineoplastic drug.Typically the chemoprotectant reduces or eliminates systemic toxicity inthe patient and/or reduces or eliminates respiratory tract toxicity inthe patient. Chemoprotectants can typically be dexrazoxane (ICRF-187),mesna (ORG-2766), ethiofos (WR2721), or a mixture thereof. Thechemoprotectant may be administered before, after, or during theadministration of the antineoplastic drug. Typically the antineoplasticdrug is a nonvesicant, a moderate vesicant, or a severe vesicant.Typically the antineoplastic drug comprises bleomycin, doxorubicin, ormitomycin-C.

An additional embodiment of the invention includes a method for treatinga patient having a neoplasm comprising: administering a safe andeffective amount of a non-encapsulated antineoplastic drug to thepatient by inhalation, the drug selected from the group consisting ofantineoplastic drugs wherein when 0.2 ml of the drug is injectedintradermally to rats, at the clinical concentration for IV use inhumans: (a) at least one lesion per rat results which is greater than 20mm² in area fourteen days after the intradermal injection; and (b) atleast 50% of the tested rats have these lesions. In some typicalembodiments when the drug is doxorubicin or vinblastine sulfate, thedrug is inhaled in the absence of perfluorocarbon. Typical diseasestreated include a neoplasm such as a pulmonary neoplasm, a neoplasm ofthe head and neck, or other systemic neoplasm. The drug may typically beinhaled as inhaled as a liquid aerosol or as a powdered aerosol. Mammalanimals and humans are typical patients treated with the method. Thedrug may typically be selected from the group consisting of doxorubicin,daunorubicin, methoxymorpholino-doxorubicin, epirubicin,cyanomorpholinyl doxorubicin, and idarubicin. When the drug is a vincaalkaloid it is typically selected from the group consisting ofvincristine, vinorelbine, vindesine, and vinblastine. Other useful drugstypically include the alkylating agents mechlorethamine, mithramycin anddactinomycin. Still additional useful drugs typically include bisantreneand amsacrine. The drug can typically be a taxane such as doxitaxel orpaclitaxel.

Another embodiment of the invention includes a method for treating apatient having a neoplasm comprising: administering an effective amountof a highly toxic non-encapsulated antineoplastic drug to a patient byinhalation, wherein the molecular weight of the drug is above 350, andthe drug has no substantial pulmonary toxicity. Typically the neoplasmis a pulmonary neoplasm, a neoplasm of the head and neck, or a systemicneoplasm. The drug may be inhaled as a liquid aerosol or as a powderedaerosol. Typically the drug has a protein binding affinity of 25% , 50%or more. In one aspect the drug is typically selected from the groupcomprising doxorubicin, epirubicin, daunorubicin,methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, andidarubicin. If the drug is doxorubicin or vinca alkaloid it may betypically be administered without the presence of a perfluorocarbon.Typically the vinca alkaloid is selected from the group consisting ofvincristine, vinorelbine, vindesine, and vinblastine. Typical alkylatingagent type drugs include mechlorethamine, mithramycin, dactinomycin.Other topoisomerase II inhibitors include bisantrene or amsacrine.

An additional embodiment includes a method for treating a patient for aneoplasm by the steps of administering an effective amount of anantineoplastic drug to the patient by inhalation; and administering apharmaceutically effective amount of the same and/or differentantineoplastic drug to the patient parenterally. The patient may betreated with one or more adjunct therapies including radiotherapy,immunotherapy, gene therapy, chemoprotective drug therapy.

A further embodiment includes a method for treating a patient for aneoplasm including the steps of administering an effective amount of anantineoplastic drug to the patient by inhalation; and administering aneffective amount of the same and/or different antineoplastic drug to thepatient by isolated organ perfusion. The patient may be treated by oneor more adjunct therapies including radiotherapy, immunotherapy, genetherapy, and chemoprotective drug therapy.

An further embodiment includes a method for treating a patient for apulmonary neoplasm by the steps of (1) selecting one or moreantineoplastic drugs efficacious in treating the neoplasm and having aresidence time in the pulmonary mucosa sufficient to be efficacious inthe treatment of the pulmonary neoplasm; and (2) administering thedrug(s) to the patient by inhalation in a non-encapsulated form.Typically when 0.2 ml of at least one of the drugs is injectedintradermally to rats, at the clinical concentration for parenteral usein humans: a lesion results which is greater than 20 mm² in areafourteen days after the intradermal injection; and B. at least 50% ofthe tested rats have these lesions. Typically the molecular weight of atleast one of the selected drugs is above 350.

A still further embodiment includes a method of use including the stepsof administering one or more non-encapsulated highly toxic anticancerdrugs to a mammal by inhalation, wherein at least one of the drugscomprises a severe vesicant.

Another embodiment is an apparatus for treating a patient for a neoplasmby inhalation that is a combination of a nebulizer and a formulation fortreating a neoplasm, the formulation including (1) a non-encapsulatedanticancer drug, and (2) a pharmaceutically acceptable carrier; whereinwhen 0.2 ml of the formulation is injected intradermally to rats, at theclinical concentration for parenteral use in humans: (a) a lesionresults which is greater than about 20 mm² in area fourteen days afterthe intradermal injection; and (b) at least 50% of the tested rats havethese lesions. A further embodiment includes a formulation which wheninjected results in a lesion which is greater than about 10 mm² in area30 days after the intradermal injection; and at least about 50% of thetested rats have these longer lasting lesions. Typically the formulationincludes an anthracycline. Anthracyclines may be selected from the groupconsisting of epirubicin, daunorubicin, methoxymorpholinodoxorubicin,cyanomorpholinyl doxorubicin, doxorubicin, and idarubicin. Theformulation also typically and contain a vinca alkaloid. Vinca alkaloidsmay be selected from the group consisting of vincristine, vinorelbine,vinorelbine, vindesine, and vinblastine. Alternately, the formulationmay contain vesicant selected from the group consisting ofmechlorethamine, mithramycin, and dactinomycin; or bisantrene oramsacrine. Typically the formulation can also contain a taxane which istypically a paclitaxel or doxytaxel.

Another embodiment of the invention includes an inhalation mask foradministering aerosols to an patient comprising: means for enclosing themouth and nose of the patient, having an open end and a closed end, theopen end adapted for placing over the mouth and nose of the patient;upper and lower holes in the closed end adapted for insertion of a noseoutlet tube and a mouth inhalation tube; the nose outlet tube attachedto the upper hole, adapted to accept exhaled breath from the nose of thepatient; a one way valve in the nose tube adapted to allow exhalationbut not inhalation; the mouth inhalation tube having an outer and aninner end, partially inserted through the lower hole, the inner endcontinuing to end at the rear of the patients mouth, the inhalation tubeend cut at an angle so that the lower portion extends further into thepatients mouth than the upper portion and adapted to fit the curvatureof the rear of the patients mouth; and a y-adapter attached to the outerend of the mouth inhalation tube. The mask typically will have amoderate vesicant or a severe vesicant present in the inhalation tube.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the plasma drug concentration time profile for dog #101having doxorubicin administered intravenously (IV) (circles) and by thepulmonary inhalation route (IH) (squares). The vertical Y scale is theconcentration of drug in the circulatory system in ng/ml and thehorizontal X scale is time after treatment in hours.

FIG. 2 shows the plasma drug concentration time profile for dog #102having doxorubicin administered intravenously (IV) (circles) and by thepulmonary inhalation route (IH) (squares). The vertical Y scale is theconcentration of drug in the circulatory system in ng/ml and thehorizontal X scale is time after treatment in hours.

FIG. 3 shows the plasma drug concentration time profile for dog #103having doxorubicin administered intravenously (IV) (circles) and by thepulmonary inhalation route (IH) (squares). The vertical Y scale is theconcentration of drug in the circulatory system in ng/ml and thehorizontal X scale is time after treatment in hours.

FIG. 4 shows a schematic of the pulmonary delivery apparatus arrangementthat was used to administer drug to dogs by inhalation for Example 3.

FIG. 5 shows a schematic of the pulmonary delivery apparatus arrangementthat was used to administer high doses and multiple doses of drug todogs by inhalation for Example 4.

FIG. 6 shows a schematic drawing of details of a mask useful foradministering drugs by inhalation to a mammal such as a dog.

FIG. 7 shows a schematic drawing of a portable device for administrationof anticancer drugs according to the invention.

DETAILED DESCRIPTION OF THE INVENTION AND BEST MODE

The delivery of antineoplastic drugs by inhalation by the pulmonaryroute is an attractive alternative to the administration of drugs byvarious injectable methods, particularly those drugs that are given on achronic or repeated administration schedule. A cause of concern is thetoxic nature of the drugs particularly those that are cytotoxic such asthe classes represented by alkylating agents, taxanes, vinca alkaloids,platinum complexes, anthracyclines and others that are consideredparticularly toxic especially when administered outside the circulatorysystem.

Broadly, the inventors have discovered that highly toxic, vesicant andpreviously unknown nonvesicant antineoplastic drugs can be effectivelydelivered to a patient in need of treatment for neoplasms or cancers byinhalation. This route is particularly effective for treatment ofneoplasms or cancers of the pulmonary system because the highly toxicdrugs are delivered directly to the site where they are needed,providing regional doses much higher than can be achieved byconventional IV delivery. As used herein the respiratory tract includesthe oral and nasal-pharyngeal, tracheo-bronchial, and pulmonary regions.The pulmonary region is defined to include the upper and lower bronchi,bronchioles, terminal bronchioles, respiratory bronchioles, and alveoli.

An important benefit from inhalation therapy for neoplasms of the head,neck and respiratory tract, is that exposure to the rest of the body iscontrolled following administration of high doses of drug andconsequently is spared much of the adverse side effects often associatedwith high doses of systemically administered highly toxic antineoplasticdrugs, yet significantly increased doses are provided at the site of thetumor. These toxic effects include for example: cardiotoxicity,myelosuppression, thrombocytopenia, renal toxicity, and hepatic toxicitythat are often life threatening. The toxic effects are often so severethat it is not uncommon for patients to die from the effects of thesystemically administered drugs rather than from the disease for whichthey are being treated.

Broadly, vesicants as used herein include chemotherapeutic agents thatare toxic and typically cause long lasting damage to surrounding tissueif the drug is extravasated. If inadvertently delivered outside of avein, a vesicant has the potential to cause pain, cellular damageincluding cellulitis, tissue destruction (necrosis) with the formationof a long lasting sore or ulcer and sloughing of tissues that may beextensive and require skin grafting. In extreme cases extravasation ofvesicants such as doxorubicin has required surgical excision of theaffected area or amputation of the affected limb. Examples ofantineoplastic chemotherapeutic agents that are generally acceptedvesicants include alkylating agents such as mechlorethamine,dactinomycin, mithramycin; topoisomerase II inhibitors such asbisantrene, doxorubicin (adriamycin), daunorubicin, dactinomycin,amsacrine, epirubicin, daunorubicin, and idarubicin; tubulin inhibitorssuch as vincristine, vinblastine, and vindesine; and estramustine. Apartial list of vesicants is found in Table 1.

In another embodiment, vesicants as more narrowly used herein includedrugs that produce a lesion in rats, where the average lesion size isgreater than about 20 mm² in area, fourteen days after an intradermalinjection of 0.2 ml of the drug, and where 50% or more of the animalshave this size of lesion. The drug concentration for the intradermalinjection is the clinical concentration recommended by the manufacturerfor use in humans, the dose recommended in the Physicians DeskReference, 1997 (or a more current version of this reference), oranother drug manual for health specialists. If there is norecommendation by the manufacturer (for example for because the drug isnew) and there is no recommendation in the Physicians Desk Reference orsimilar drug manual for health specialists then other current medicalliterature may be used. If more than one clinical concentration isrecommended, the highest recommended clinical concentration is used.Lesion as used herein means an open sore or ulcer or sloughing off ofskin with exposure of underlying tissue.

In a yet further embodiment of the invention, 0.2 ml of a highly toxicanticancer drug (vesicant) at a dose recommended for humans (asdiscussed above) is administered intradermally to rats at aconcentration that causes the above mentioned lesion size for a moreextended period of time. That is, the lesions remain above about 10 mm²up to at least 30 days in at least 50% or more of the animals.

Nonvesicants typically are also irritating and can cause pain, but donot usually result in long lasting sores or ulcers or sloughing off oftissues except in exceptional cases. Examples include alkylating agentssuch as cyclophosphamide, bleomycin (blenoxane), carmustine, anddacarbazine; DNA crosslinking agents such as thiotepa, cisplatin,melphalan (L-PAM); antimetabolites such as cytarabine, fluorouracil(5-FU), methotrexate (MTX), and mercaptopurine (6 MP); topoisomerase IIinhibitors such as mitoxantrone; epipodophyllotoxins such as etoposide(VP-16) and teniposide (VM-26); hormonal agents such as estrogens,glucocorticosteroids, progestins, and antiestrogens; and miscellaneousagents such as asparaginase, and streptozocin.

A listing of materials usually accepted to be vesicants or nonvesicantsis provided below as Table 1—Vesicant/Nonvesicant Drug Activity.

TABLE 1 Vesicant/Non-Vesicant Drug Activity Classification VesicantNon-Vesicant Alkylating Agents Mechlorethamine^(a,c,d,e)*Cyclophosphamide (Cytoxan)^(b) Mitomycin-C^(a,c,e)* Bleomycin(Blenoxane)^(b,e) Dactinomycin^(d,e)* Carmustine^(a,b,d) Mithramycin^(d)Mithramycin^(a,b) (Plicamycin) (Plicamycin) Dacarbazine^(a,b,e) DNACrosslinking Thiotepa^(b) Agents Cisplatin^(b,e) Melphalan (L-PAM)^(b)Antimetabolites Cytarabine (ARA C)^(b) Fluorouracil (5 FU)^(b,d,e)Methotrexate (MTX)^(b) Mercaptopurine (6 MP)^(b) Topoisomerase IIBisantrene^(c,e)* Mitoxantrone^(b,e) Inhibitors (Anthracene)(Anthracene) Dactinomycin^(a,c) Esorubicin^(e) Doxorubicin^(a,b,c,d,e)*Etoposide (VP-16)^(a,b,e) (Anthracycline) (Epipodophyllotoxin)Cyanomorpholinyl Teniposide (VM-26)^(a,b,e) Doxorubicin^(e)*(Epipodophyllotoxin) Amsacrine^(a,c,e)* Epirubicin^(c,e)*Daunorubicin^(a,d,e)* Idarubicin^(a,e)* Liposomal anthracyclines^(e)Hormonal Agents Estrogens^(b) Glucocorticosteroids^(b) Progestins^(b)Antiestrogens^(b) Tubulin Inhibitors Vinblastine^(a,d,e)*Vincristine^(a,d,e)* Vinorelbine^(e)* Vindesine^(a,e)* Paclitaxel^(c,)Paclitaxel^(e,f) Miscellaneous Asparaginase^(b) (Enzyme)Aclacinomycin^(e) Streptozocin^(a,b) Menogaril^(e) ^(a)According to U.S.Pat. No. 5,602,112 ^(b)Dorr, R.T. et al, Lack of Experimental VesicantActivity for the Anticancer Agents Cisplatin, Melphalan, andMitoxantrone, Cancer Chemother. Pharmacol., Vol. 16, 1986, pp. 91-94^(c)According to Bicher, A. et al, Infusion Site Soft-Tissue InjuryAfter Paclitaxel Administration, Cancer, Vol. 76, No. 1, July 1, 1995,pp. 116-120 ^(d)Rudolph, R. et al; Etiology and Treatment ofChemotherapeutic Agent Extravasation Injuries: A Review; Journal ofClinical Oncology, Vol. 5; No. 7; July 1987; pp. 1116-1126 ^(e)Bertelli,G., Prevention and Management of Extravasation of Cytotoxic Drugs, DrugSafety, 12 (4) 1995; pp. 245-255. The listed drugs have been reported inat least one case, either clinically or experimentally, to cause tissuenecrosis after accidental extravasation. Symbol: * = vesicants, drugswith the highest potential for localized tissue damage afterextravasation ^(f)Cancer, R.T., Communications, Author Reply, Cancer,pp. 226

Typical embodiments of the invention use highly toxic antineoplasticdrugs that have similar or greater vesicating activity than those thathave been tested in animals by inhalation to date. One embodimenttypically uses severely vesicating toxic antineoplastic drugs havinghigher vesicating activity than those represented by 5-FU, β-cytosinearabinoside (Ara-C, cytarabine), mitomycin C, and cisplatin. In respectto the latter, it is disclosed that a highly toxic drug represented bythe class anthracyclines (of which doxorubicin is among the most toxic),has been administered by inhalation to a patient in need of treatmentfor neoplasms. In a further embodiment of the invention it is disclosedthat vesicants other than doxorubicin can be given to patients byinhalation. In respect to the latter, highly toxic drugs represented bythe classes vinca alkaloids, and taxanes, having similar high toxicitieshave been administered by inhalation to a patient in need of treatmentfor neoplasms. In a yet further embodiment of the invention there isdisclosed that certain antineoplastic drugs that are nonvesicants can beadministered by inhalation to a patient in need of treatment forneoplasms. In a further embodiment of the invention there are disclosedformulations and methods for applying the aforementioned highly toxicdrugs to a patient in need of treatment for pulmonary neoplasms byinhalation.

EXAMPLE 1

This example illustrates and confirms toxicity and vesicant/nonvesicantactivity of several antineoplastic drugs. The vesicant activities ofthirteen anticancer drugs were investigated (see the listing in Table 2below). Doxorubicin has traditionally been considered a vesicant (seeTable 1). Paclitaxel has previously been considered a nonvesicant, butrecent literature has advocated its classification as a vesicant. Someof the remaining drugs are traditionally considered to be vesicants andothers nonvesicants (Table 1). Day fourteen after injection was chosenas the time for comparison for vesicant activity, because lesions causedby nonvesicants should have been significantly reduced while lesionscaused by vesicants should still be large. Sterile saline solution(0.9%) for injection USP, pH 4.5-7.0, or sterile water for injection, asappropriate, was used to reconstitute the drugs.

The drugs used for the vesicant activity tests are identified asfollows: doxorubicin (Adriamycin PFS), a red liquid in glass vials, noformulation was necessary; cisplatin (Platinol-AQ™), a liquid in glassvials, no formulation was necessary; Paclitaxel (Taxol™), a liquid inglass vials, formulated with saline solution; fluorouracil, a clearyellow liquid in glass vials, no formulation was necessary; cytarabine(Cytosar-U™), a white powder in glass vials, formulated with water;9-aminocamptothecin (9-AC colloidal suspension), a yellow powder inglass vials, formulated with water; cyclophosphamide (Cytoxan™), ayellow powder in glass vials, formulated with a saline/water mixture;carboplatin (Paraplatin™), a white powder in injectable vials,formulated with saline solution; etoposide (VePesid™), a clear liquid inglass vials, formulated with saline solution; bleomycin (bleomycinsulfate, USP), a lyophilized powder tablet in glass vials, formulatedwith saline solution; vincristine (vincristine sulfate), an injectableliquid in injection vials, no formulation necessary; vinorelbinetartrate (Navelbine™), a clear liquid in glass vials, diluted with waterper package instructions; and mitomycin (Mutamycin™), a gray crystallinepowder in glass amber bottles, formulated with water. All of these drugswere reconstituted following standard and known methods recommended bythe manufacturers.

The tests for vesicant activity were conducted using Sprague Dawley rats(7-8 weeks old having 150-200 g of body weight. Each received a singleintradermal injection of the test drug at the recommended clinicalconcentration (listed below in Table 2) in the right dorsum.Approximately 24 hours prior to administration, the hair was removedfrom the dorsum using clippers and a depilatory agent. Each 0.2 mlinjection was given with a 1 ml syringe and 27 gauge needle. All drugsolutions were either isotonic or slightly hypertonic.

TABLE 2 Formulations administered for Vesicant Tests Formulation TestFormulation Concentration 1 Doxorubicin 2 mg/ml 2 Platinol 1 mg/ml 3Paclitaxel 1.2 mg/ml 4 Fluorouracil 50 mg/ml 5 Cytarabine 100 mg/ml 69-aminocamptothecin 100 μg/ml 7 Cyclophosphamide 20 mg/ml 8 Carboplatin10 mg/ml 9 Etoposide 0.4 mg/ml 10 Bleomycin 20 units/ml 11 Vincristine 1mg/ml 12 Vinorelbine 3 mg/ml 13 Mitomycin-C 0.5 mg/ml

Table 3 below is a tabulation of the resultant lesion sizes thatdeveloped from intradermal injections of the above drugs. Lesion sizeswere measured as more fully discussed below.

TABLE 3 Individual Lesion Size Measurements (mm²) (see text forexplanation of measurements) Animal Day of Test (post injection) NumberTest Drug 6 8 10 13 15 17 20 22 24 27 29 31 34 36 38 41 101 Doxorubicin— 21.4 33.9 57.0 42.9 34.0 35.4 27.2 32.2 31.7 31.7 17.1 8.3 6.3 6.7 4.5102 Doxorubicin — 18.8 23.5 10.9 12.9 9.7 10.2 9.9 11.8 10.5 9.9 10.22.8 — — — 103 Doxorubicin — 36.5 58.0 82.9 45.5 37.7 28.1 26.9 21.0 23.918.6 16.2 12.5 10.3 7.6 6.1 104 Doxorubicin — 44.6 27.3 33.6 17.7 21.728.1 19.5 16.6 16.1 18.9 13.9 9.0 5.1 4.5 4.0 105 Doxorubicin — 33.935.2 33.3 35.1 29.4 30.2 29.7 25.0 24.4 24.8 23.5 24.0 24.5 21.6 22.0106 Doxorubicin — 30.6 43.2 32.2 35.2 34.4 29.2 30.2 15.5 16.0 15.4 14.516.2 14.8 14.3 5.2 107 Doxorubicin — 26.1 39.7 38.6 33.8 31.3 25.0 22.021.6 19.8 22.4 21.5 20.9 21.0 18.4 18.9 111 Platinol 26.9 18.7 18.0 11.821.2 17.1 6.9 1.5 1.0 — — — — — — — 112 Platinol 35.5 20.3 20.8 15.516.1 16.2 16.5 4.1 — — — — — — — — 113 Platinol 15.3 15.8 14.6 10.1 9.19.0 8.3 2.9 2.6 1.7 — — — — — — 114 Platinol 17.2 11.3 13.2 9.7 9.2 10.310.5 9.1 — — — — — — — — 115 Platinol 26.8 25.0 14.8 21.8 18.0 15.0 16.016.0 2.1 1.7 1.4 — — — — — 116 Platinol 21.8 20.7 12.2 11.8 12.9 12.68.4 10.8 8.5 8.4 — — — — — — 117 Platinol 24.9 21.3 16.7 15.1 16.4 14.814.3 12.2 12.5 2.8 — — — — — — 121 Taxol 23.7 21.6 21.2 18.9 3.5 — — — —— — — — — — — 122 Taxol 37.3 30.1 26.1 25.2 21.8 21.7 5.6 2.1 1.8 — — —— — — — 123 Taxol 7.9 5.9 4.3 1.1 1.2 — — — — — — — — — — — 124 Taxol43.2 36.9 32.9 30.6 29.0 28.5 — — — — — — — — — — 125 Taxol 38.4 34.628.6 22.1 5.9 — — — — — — — — — — — 126 Taxol 69.5 59.5 53.3 53.3 42.95.2 — — — — — — — — — — 127 Taxol 45.9 23.1 16.1 14.3 8.4 5.0 — — — — —— — — — — 131 Fluorouracil 29.0 19.9 13.5 11.2 14.3 11.6 8.3 2.0 — — — —— — — — 132 Fluorouracil 17.1 16.2 11.8 3.0 — — — — — — — — — — — — 133Fluorouracil 27.0 23.8 17.4 17.6 17.9 0.5 — — — — — — — — — — 134Fluorouracil 21.9 18.9 17.0 6.7 — — — — — — — — — — — — 135 Fluorouracil20.5 27.5 21.4 4.5 — — — — — — — — — — — — 136 Fluorouracil 23.5 14.010.1 9.5 8.0 7.8 1.8 — — — — — — — — — 137 Fluorouracil 20.5 7.0 6.2 4.84.6 3.8 — — — — — — — — — — 151 9-aminocamptothecin 21.8 15.8 16.0 14.59.0 19.9 — — — — — — — — — — 152 9-aminocamptothecin 8.6 4.4 5.4 3.7 4.03.6 — — — — — — — — — — 153 9-aminocamptothecin 4.4 2.6 2.9 1.3 1.1 — —— — — — — — — — — 154 9-aminocamptothecin 23.8 21.9 20.9 19.8 15.5 18.6— — — — — — — — — — 155 9-aminocamptothecin 12.5 7.9 10.0 9.6 9.9 0.6 —— — — — — — — — — 156 9-aminocamptothecin 12.6 10.4 5.8 4.6 3.1 — — — —— — — — — — — 157 9-aminocamptothecin 12.5 7.8 5.2 3.7 — — — — — — — — —— — — 161 Cyclophosphamide 16.4 13.6 11.3 9.4 8.3 8.6 — — — — — — — — —— 162 Cyclophosphamide 35.1 33.8 23.2 3.5 1.4 — — — — — — — — — — — 163Cyclophosphamide 25.8 18.9 21.0 19.3 17.2 17.2 12.1 12.5 14.0 7.8 2.4 —— — — — 165 Cyclophosphamide 19.4 18.2 17.9 17.4 16.6 15.9 13.2 12.212.7 7.5 1.8 1.5 — — — — 166 Cyclophosphamide 31.8 33.8 25.4 23.9 11.92.2 — — — — — — — — — — 167 Cyclophosphamide 25.2 19.7 19.1 19.3 18.918.9 17.4 14.6 15.6 4.1 2.0 — — — — — 171 Carboplatin 16.2 17.3 12.210.9 10.4 8.1 4.6 0.8 — — — — — — — — 172 Carboplatin 9.0 5.1 21.9 17.57.6 4.1 5.2 6.2 5.9 5.2 3.2 2.6 — — — — 173 Carboplatin 24.8 23.4 17.720.5 18.5 16.0 8.6 3.4 0.8 0.6 — — — — — — 174 Carboplatin 31.9 23.118.2 24.2 27.0 19.4 15.5 13.1 11.2 4.0 1.5 — — — — — 175 Carboplatin20.5 24.5 22.1 13.4 20.4 16.8 5.4 4.9 1.8 1.2 — — — — — — 177Carboplatin 42.9 39.1 30.1 31.7 32.7 32.6 35.4 34.7 34.6 23.9 25.2 25.719.2 0.6 — — 181 Etoposide 21.1 15.0 11.2 9.2 9.8 9.0 2.9 — — — — — — —— — 182 Etoposide — — 3.8 2.4 2.0 1.7 1.1 — — — — — — — — — 183Etoposide 1.3 4.6 3.1 2.9 3.8 1.2 — — — — — — — — — — 184 Etoposide —9.6 4.7 — — — — — — — — — — — — — 185 Etoposide 5.9 6.0 6.0 2.6 2.1 2.0— — — — — — — — — — 186 Etoposide 10.6 14.1 7.7 6.6 8.4 3.8 1.7 — — — —— — — — — 187 Etoposide 6.5 10.0 9.3 5.3 5.4 5.1 3.5 — — — — — — — — —191 Bleomycin 8.2 5.1 8.8 2.2 1.6 — — — — — — — — — — — 192 Bleomycin21.1 15.3 10.8 16.3 3.8 1.3 — — — — — — — — — — 193 Bleomycin 23.5 18.915.4 13.8 5.5 1.3 — — — — — — — — — — 194 Bleomycin — 5.0 3.2 1.0 2.3 —— — — — — — — — — — 195 Bleomycin 7.7 6.5 6.7 6.5 7.0 3.2 1.3 — — — — —— — — — 196 Bleomycin 13.4 7.8 6.8 7.2 6.6 0.7 — — — — — — — — — — 197Bleomycin 27.0 27.0 26.0 25.2 26.0 24.0 1.0 0.6 — 0.4 — — — — — — 202Vincristine — — 469.0 307.7 227.7 160.5 109.2 93.3 93.6 83.6 67.2 57.947.5 40.3 40.2 34.0 203 Vincristine — — — 165.3 158.5 67.0 29.7 28.624.7 21.1 22.0 22.8 27.5 30.6 21.2 13.8 205 Vincristine — — — 130.4136.2 111.6 76.1 61.5 58.0 42.0 26.5 18.1 12.6 5.3 4.2 1.3 206Vincristine — — 145.6 96.9 81.6 96.1 66.7 59.2 51.3 13.0 7.2 — — — — —211 Vinorelbine — 16.8 421.7 315.2 289.7 274.6 250.8 200.8 170.8 159.1237.2 243.6 243.1 219.4 180.6 149.0 212 Vinorelbine — 436.7 422.1 426.5408.5 347.6 316.8 298.8 292.4 282.0 251.0 81.3 82.0 83.8 45.8 17.2 213Vinorelbine — 402.2 429.0 352.6 323.4 372.9 366.3 311.6 312.1 299.2302.3 294.0 102.7 137.7 212.1 192.1 214 Vinorelbine — 322.1 261.6 283.6293.9 241.7 227.0 221.9 227.2 105.0 86.1 72.5 65.3 71.4 52.5 62.0 215Vinorelbine — 297.0 277.8 269.7 225.3 204.2 82.5 69.8 67.8 40.0 28.431.9 17.4 19.2 14.0 14.5 216 Vinorelbine — 348.3 325.1 308.1 288.9 297.0278.7 255.9 269.3 255.8 134.9 103.7 61.2 95.7 123.2 108.2 217Vinorelbine — 275.1 309.6 272.1 249.0 217.1 208.1 209.3 190.7 175.5173.2 172.0 173.4 157.3 187.7 155.5 221 Mutamycin 45.0 46.8 47.5 77.048.2 38.8 45.4 41.6 40.3 28.6 9.6 6.4 4.1 0.7 — — 222 Mutamycin 50.450.4 49.6 41.9 45.1 34.8 42.0 46.2 9.9 9.3 7.5 — — — — — 223 Mutamycin98.3 73.0 79.1 79.8 71.0 64.6 66.0 28.5 17.6 24.3 28.2 1.1 — — — — 224Mutamycin 58.2 82.4 62.6 78.8 73.3 66.1 53.9 36.9 32.9 31.2 19.8 16.815.5 16.8 21.0 25.6 225 Mutamycin 28.1 24.2 28.0 19.8 29.8 23.0 12.813.2 11.9 8.5 6.6 7.2 2.0 1.5 — — 226 Mutamycin 61.3 53.3 59.9 49.7 48.938.0 39.5 42.1 40.6 23.0 5.6 4.8 4.6 4.6 1.2 — 227 Mutamycin 36.0 35.837.8 37.8 39.7 33.8 31.1 13.9 10.9 7.9 8.1 2.9 — — — —

Results were as follows:

1. Abrasions of the dorsal body were observed in a majority of animalsfor all drugs except cytarabine.

2. Alopecia of the dorsal body was seen for doxorubicin (3/7),paclitaxel (7/7), and fluorouracil (7/7), etoposide (7/7), bleomycin(7/7), vincristine (2/7), vinorelbine (7/7), and mitomycin-C (mutamycin)(4/7).

3. Discoloration of the skin around the site of injection was seen fordoxorubicin, vincristine, vinorelbine, and mitomycin-C.

4. Rough coat was observed in fluorouracil (1/7), vincristine (4/7), andvinorelbine (2/7).

5. Systemic effects were observed only for vincristine. Three animalshad to be removed from the tests because of their poor condition.

6. Slight edema was observed for all groups. Moderate edema was observedin doxorubicin, vincristine, vinorelbine, and mitomycin-C treatedanimals. Severe edema was observed only for animals treated withvinorelbine and vincristine.

7. Severe erythema was seen for all drugs except for cisplatin(platinol) and cytarabine.

8. Dermal lesions were observed for all drugs except for cytarabine.Most lesions appeared between days 6 and 10 and maximized in size duringthe first seven days, and then gradually decreased in size. Doxorubicin,vincristine, vinorelbine, and mitomycin-C were the only drugs thatcaused lesions that lasted until the test termination at day 41.However, for mitomycin-C only one animal of seven still had lesions tothe end of the test. One rat (#123) injected with paclitaxel (taxol) wasdetermined to not have received a proper intradermal injection and wasnot used in the results.

Dermal lesions at the site of injection were determined to be the bestand most objective measure and predictor of vesicant activity for adrug. Lesion size was quantitated by micrometer measurements of the twolargest perpendicular diameters and the two values multiplied to yield alesion area in mm². Lesions were regularly evaluated and scored as shownin Table 3.

A vesicant as determined by the methods used herein is defined ascausing a lesion of at least about 20 mm², in at least one half of theanimals, two weeks after injection (day 15 in Table 3). Table 3 showsthat doxorubicin, paclitaxel, carboplatin, vincristine, vinorelbine, andmitomycin-C fulfill these criteria. Cisplatin, etoposide, bleomycin,cytarabine, cyclophosphamide, fluorouracil, and 9-aminocamptothecin arethus categorized as non-vesicants.

A moderate vesicant as determined by the methods used herein is definedas causing a lesion of at least about 20 mm², in at least one half ofthe animals, two weeks after injection (day 15 in Table 3), but lessthan half of the animals will have lesions greater than about 10 mm² 30days after injection (day 31 in Table 3). The data from Table 3 showsthat paclitaxel, carboplatin, and mitomycin-C fulfill these criteria. Ofthese, mitomycin-C has been determined to exhibit substantial pulmonarytoxicity.

A severe vesicant as determined by the methods used herein is defined ascausing a lesion of at least about 20 mm², in at least one-half of theanimals, two weeks after injection (day 15 in Table 3), and at leastone-half of the animals will still have lesions greater than about 10mm², 30 days after injection (day 31 in Table 3). Table 3 shows thatdoxorubicin, vincristine, and vinorelbine satisfy these criteria.

Surprisingly it has now been found that moderate to severe vesicants canbe used for inhalation therapy of cancer as revealed in the discussionand examples below. Further, other highly toxic drugs, although nothaving the severity of reaction of moderate to severe vesicants havealso been found to be useful in the treatment of cancer by inhalation asfurther discussed below.

Antineoplastic drugs that are highly toxic and useful in an embodimentof the present invention include the anthracyclines (e.g. doxorubicin,epirubicin, idarubicin, methoxy-morpholinodoxorubicin, daunorubicin, andthe like); vinca alkaloids (e.g. vincristine, vinblastine, vindesine,and the like); alkylating agents (e.g. mechlorethamine and the like);carboplatin; nitrogen mustards (e.g. melphalan and the like),topoisomerase I inhibitors (e.g. 9-aminocamptothecin, camptothecin,topotecan, irenotecan, 9-NO-camptothecin, and the like); topoisomeraseII inhibitors (e.g. etoposide, teniposide, and the like); and paclitaxeland the like. These and other useful compounds are further discussedbelow.

In yet a further embodiment of the invention, there are disclosedformulations and methods for applying an appropriate selection of highlytoxic drugs that are efficacious in treating the neoplasm or cancer,that are applied by inhalation and that reside in the pulmonary systemfor a time sufficient to increase the exposure of the neoplasm to thedrug, yet allow a reduction and/or controlled systemic exposure of thedrug, and provide a more efficacious treatment for pulmonary neoplasms.

In a further embodiment of the invention, it is disclosed that it ispossible to deliver antineoplastic drugs by the pulmonary route as ameans to provide systemic treatment of distant tumors. The inventorshave shown that for selected drugs inhalation can be used as anoninvasive route of delivery without causing significant toxicity tothe respiratory tract. This is in contrast with the prior art that usedinhalation for treatment of disease in the respiratory system.

As used herein the term patient includes a mammal including, but notlimited to, mice, rats, cats, horses, dogs, cattle, sheep, apes,monkeys, goats, camels, other domesticated animals, and of coursehumans.

Administration by inhalation as used herein includes the respiratoryadministration of drugs as either liquid aerosols or powdered aerosolssuspended in a gas such as air or other nonreactive carrier gas that isinhaled by a patient. Non-encapsulated drug as used herein means thatthe antineoplastic drug is not enclosed within a liposome, or within apolymeric matrix, or within an enclosing shell. Where the termencapsulated drug is used herein the term means that the antineoplasticdrug is enclosed within a liposome, within a polymeric matrix, or withinan enclosing shell. However, in some embodiments the antineoplastic drugmay be coupled to various molecules yet is still not enclosed in aliposome, matrix or shell as further discussed below.

In other embodiments of the invention the antineoplastic drugs disclosedherein may be coupled with other molecules through ester bonds. Enzymespresent in the respiratory system later cleave the ester bonds. Onepurpose of coupling the antineoplastic drugs through an ester bond is toincrease the residence time of the antineoplastic drug in the pulmonarysystem. Increased residence time is achieved by: first, an increase inmolecular weight due to the attached molecule; second, by appropriatechoice of a coupled molecule; third, other factors such as for examplecharge, solubility, shape, particle size of the delivered aerosol, andprotein binding can be modified and used to alter the diffusion of thedrug. Molecules useful for esterification with the drug includealpha-hydroxy acids and oligomers thereof, vitamins such as vitamins A,C, E and retinoic acid, other retinoids, ceramides, saturated orunsaturated fatty acids such as linoleic acid and glycerin. Preferredmolecules for esterification are those naturally present in the area ofdeposition of the active drug in the respiratory tract.

As a demonstration of the proof of concept, doxorubicin was used in aseries of tests. Doxorubicin was chosen as an initial test agent sinceit is one of most cytotoxic and potent vesicants of all anti-neoplasticagents considered in the broad embodiment (pulmonary delivery ofanti-neoplastic drugs) of the present invention. Based on positiveoutcome of these proof of concept studies, anticancer drugs from othermajor classes were simultaneously tested. Results consistently showedthat using the approach and methods described in this invention the drugcould be safely and effectively delivered by inhalation. In Examples 2and 3 below, doxorubicin was administered to three dogs (beagles) byboth the pulmonary and intravenous route of administration. The dogswere given a clinically effective dosage of the drug and the amount ofthe drug appearing in the blood system was measured.

An anthracycline antineoplastic drug, a salt of doxorubicin, doxorubicinHCl, available from Farmitalia Carlo Erba (now Pharmacia & Upjohn),Milan, Italy, was used in some of the examples herein. The liquidformulation that was administered to the dogs by inhalation of anaerosol was obtained by mixing the doxorubicin hydrochloride with amixture of ethanol/water at a doxorubicin concentration of approximately15-25 mg/ml. Typically solutions of 5-75% ethanol are preferred.Water/ethanol ratios may be adjusted to select the desired concentrationof doxorubicin and the desired particle size of the aerosol.

EXAMPLE 2

Three adult, male, beagle dogs were used in the tests. The dogs(designated dog 101, 102, and 103) had body weights of 10.66, 10.24, and10.02 kg respectively . As used herein “m²” used alone with reference todose refers to square meters in terms of the body surface area of atreated animal or patient, at other times it is qualified in terms oflung surface area. The dogs were given a slow IV infusion treatment ofthe anthracycline drug doxorubicin HCl at the recommended initialclinical dose (for dogs) of 20 mg/m² or 1 mg/kg of body weight. A 1mg/ml drug solution was administered at a rate of 2.0 ml/kg/hr for 30minutes. The 30-minute infusion interval simulated the time/doseexposure relationship of the inhalation group in Example 3 below. Aseries of blood samples were taken to characterize the IVpharmacokinetics at predose, 2, 5, 10, 30, 60, 90 minutes and 2, 4, 6,12, 18, and 36 hours post dosing. Additional blood samples werecollected for clinical pathology evaluations on days 3 and 7 of the IVtreatment. Changes in blood chemistry and hematology were as expectedwith administration of doxorubicin HCl at these doses.

EXAMPLE 3

The three dogs used in Example 2 were allowed a one-week washout periodbefore being subjected to exposure to the anthracycline drug doxorubicinHCl by inhalation. The dogs were acclimated to wearing masks foradministration of the aerosol prior to treatment. The dogs were exposedto an aerosol concentration of drug sufficient to deposit a total doseof about 10 mg (1 mg/kg). Based on aerosol dosimetry models,approximately one half of this dose was deposited within the respiratorytract. The total dose was about equal to the dosage administered by IVinfusion. The dose was calculated using the following equation:

Dose={Drug Conc. (mg/liter)×Mean minute Vol. (liter/min)×ExposureDuration (min)×Total Deposition Fraction (%)}÷Body Weight (kg)

wherein

Mean Min. Vol.=Tidal volume×minute respiratory rate

Exposure Duration=30 min

Mean Body Weight=weight in kg for each dog

Total Deposition Fraction=60% (determined by particle size andrespiratory tract deposition models from the published literature suchas “Respiratory Tract Deposition of Inhaled Polydisperse Aerosols inBeagle Dogs”, R. G. Cuddihy et al, Aerosol Science, Vol 4, pp. 35-45(1973) and “Deposition and Retention Models for Internal Dosimetry ofthe Human Respiratory Tract”, Task Group on Lung Dynamics, HealthPhysics, Vol. 12, pp. 173-207 (1966).

Pulmonary function measurements (respiratory rate, tidal volume, andminute volume (calculated)) were monitored during a 30 minute inhalationexposure session. These data provided an estimate of each animal'sinspired volume during exposure, and were used to calculate the mass ofdrug deposited in the respiratory tract.

A series of blood samples were collected at the end of the exposure tocharacterize the pharmacokinetics. Clinical pathology evaluations wereconducted on the third day. All three dogs were necropsied on the thirdday.

Referring now to FIG. 4, the drug formulation was administered to thedogs of Example 3 with drug exposure system 400. The drug wasaerosolized with two Pari LC Jet Plus™ nebulizers 401. The nebulizer wasfilled with a solution of 15 mg doxorubicin per ml of 50% water/50%ethanol. The output of each nebulizer 401 was continuous and set toprovide the required concentration of aerosol in attached plenum 405.The nebulizers 401 were attached directly to plenum 405 that had avolume of approximately 90 liters . Plenum 405 was connected by fourtubes 407 to four venturi 409, respectively, and subsequently connectedto four Y-fittings 413 by additional tubing 411. Typical venturi wereused to measure the inhaled volume of drug formulation. One end of eachof the Y-fittings 411 interfaced with a dog breathing mask 415 while theother end of Y-fitting 411 was connected to tubing 417 leading to anexhaust pump 419. During the tests three dogs 418 were fitted with threeof the breathing masks 415. A collection filter 421 was placed in theremaining mask 415. A vacuum pump 423 that drew 1 liter per minute ofair for 3 minutes was used in the place of a dog to draw aerosol inorder to monitor and measure the amount of drug administered. The vacuumpump was activated four times during the 30-minute administration ofdrug to the dogs and the amount of drug trapped by the filter set forthin Table 5 below.

A flow of air was supplied to each of the nebulizers 401 from a supplyof air 425 via lines 427. Additional air for providing a bias flow ofair through the system and for the breathing requirements of the dogswas provided from air supply 425 by supply lines 429 connected to oneway valves 431. The one way valves 431 were connected to the upperportion of the nebulizers 401. This additional supply of air provided acontinuous flow of air through the system 400 from the air supply 425 tothe exhaust pump 417. Alternatively one could eliminate the extra supplyof air from supply lines 429 to one way valves 431 and let ambient roomair enter the one way valves from the suction action of the nebulizers401. A Hepa filter 441 mounted to the top of plenum 405 allowed room airto flow in and out of plenum 405 and assured that there was alwaysambient pressure in the plenum. There was a continuous flow of aircontaining the aerosol past the masks of the dogs and the dogs were ableto breathe air containing the aerosol on demand. An inner tube 621located within dog breathing mask 415 extended into the mouth of thedogs and was provided with an extension 633 at its lower portion thatserved to depress the tongue of the dogs to provide an open airway forbreathing. See the discussion of FIG. 6 below.

Each of the four venturi 409 were connected by line 441 to a pressuretransducer 443 (the one shown is typical for the four venturi) that wasused to measure pressure differences across the venturi. The pressuretransducers 443 were connected by line 445 to an analog amplifier 447 toincrease the output signal and prepare the signal sent via line 449 tocomputer system 451. Computer system 451 is a desk model PC of typicaldesign in the industry and can be used in conjunction with a BUXCO orPO-NE-MAH software program to calculate the uptake of air containingaerosol and thus the drug dosage by each of the dogs.

Table 4 below summarizes the exposure data for doxorubicinadministration to dogs from Example 3. The total mass for each dog wasdetermined. The total inhaled volume of air for the 30 minute drugadministration was measured in liters. The aerosol concentration in mgof drug/liter of air (mg/l) was determined from calibration tests doneearlier. A total deposition fraction of 60% was calculated (Ascalculated 30% for the inhaled dose was deposited in the conductingupper airways and peripheral lung while and additional 30% was depositedin the oral-pharyngeal region) based on the measured doxorubicin aerosolparticle size and the published literature (see references cited above).

Thus about 25%-30% of the administered doxorubicin was deposited andavailable to the pulmonary region. Since the drug was administered inits salt form, a correction for the chlorine portion of the molecule wasmade. As shown in the Table 4 this resulted in an applied dose of 0.51,0.60, and 0.57 mg/kg to the pulmonary region of dogs 101, 102, and 103respectively

Filter data obtained from analysis of drug deposited on a filter 421placed in a fourth mask 415 are shown in Table 5 for four differentmeasurements . The drug mass collected on the filter was corrected forthe chlorine portion of the doxorubicin salt. Finally, the doxorubicinconcentration in the three liters of air drawn into each mask wasdetermined in mg/l. The four figures were averaged to obtain a meandoxorubicin aerosol concentration of 0.218 mg/l.

Table 6 shows data and calculations that verify the figures of Table 4.The dog weight and breath volumes measured for Table 4 are used.However, the mean doxorubicin concentration that was obtained from thefilter data shown in Table 5 was used to calculate doxorubicinconcentrations. Making calculations with the data as in Table 4, theinhaled dose for each dog was calculated. The inhaled dose was reducedby 40% as before to obtain the total dose deposited, and reduced by 50%again to obtain the total deposited pulmonary dose. The pulmonary dosesobtained by this method of 0.47, 0.56, and 0.53 mg/kg for dogs 101, 102,and 103 respectively compare well with the earlier calculated figures inTable 4.

TABLE 4 TOTAL MASS DATA Total Inhaled Vol. Inhaled Air Inhaled DepositedPulmonary Dog Weight (l) Aerosol Deposition Test Art. Dose Dose Dose DogNo. (kg) For 30 Min. Conc. (mg/l) Fraction Fraction (mg/kg) (mg/kg)(mg/kg) 101 10.66 77.5 0.250 0.60 0.937 1.70 1.02 0.51 102 10.24 86.80.250 0.60 0.937 1.99 1.19 0.60 103 10.02 80.8 0.250 0.60 0.937 1.891.13 0.57 A B C D E

TABLE 5 FILTER DATA Sample Weight Total Dox. Sample Vol. GainDoxorubicin Conc. Conc. Ratio No. (liter) (mg) mass (mg) (mg/l) (mg/l)Dox/Total 1 3 0.78 × 0.70 0.260 0.233 0.897 .937 2 3 0.72 × 0.61 0.2400.203 0.847 .937 3 3 0.73 × 0.62 0.243 0.207 0.849 .937 4 3 0.77 × 0.680.257 0.227 0.883 .937 Mean 0.250 0.218 0.869 A B C D

TABLE 6 ANALYTICAL DATA Total Dog Inhaled Aerosol Inhaled DepositedPulmonary Dog Weight Vol. Conc. Dose Dose Dose No. (kg) (l) (mg/l)(mg/kg) (mg/kg) (mg/kg) 101 10.66 77.5 0.218 1.58 0.95 0.47 102 10.2486.8 0.218 1.85 1.11 0.56 103 10.02 80.8 0.218 1.76 1.06 0.53 A B C

Surprisingly it was found that free non-encapsulated doxorubicinadministered by the pulmonary route was not rapidly cleared from thelung. FIGS. 1, 2 and 3 show examples of the type of results achievedwhen cytotoxic anticancer drugs were given by inhalation. Highefficiency nebulization systems as shown in FIGS. 4 and 5 were used todeliver a large percentage of aerosolized drug to the pulmonary regionof the respiratory tract. Doses equal to or greater than those thatcause toxicity when given IV, were only moderately absorbed into theblood following pulmonary delivery and caused little to no direct orsystemic toxicity after a single exposure at this dose.

As can be seen from FIGS. 1, 2 and 3, the pulmonary route administereddoxorubicin achieved a consistently lower level of doxorubicin insystemic blood, with peak blood levels being over an order of magnitudelower following inhalation exposure. The initial concentration ofdoxorubicin at 2 minutes was about 1.5 orders of magnitude larger whenadministered IV than by the pulmonary route. Later, after about 4 hours,the systemic doxorubicin level was about six times higher for the IVadministered drug. This suggests that free doxorubicin remained in thelung for an extended period of time and slowly passed through the mucosainto systemic circulation. This reduces the systemic toxic effects ofthe drug and allows its concentration in the lung for more effectivetreatment of respiratory tract associated neoplasms while reducingoverall systemic toxic effects. It is believed that the toxic effects ofdoxorubicin to tissues outside the lung are as a result of theaforementioned high levels of systemic drug concentration following IVtreatment.

Another surprising finding was that doxorubicin administered by thepulmonary route did not produce the severe toxic effects on therespiratory tract (including the oral and nasal-pharyngeal,tracheo-bronchial, and pulmonary regions). As was noted earlier,doxorubicin belongs to the anthracycline class of drugs that aretypically very toxic. In particular doxorubicin is one of the most toxicdrugs in the class, yet when the dogs in the test were necropsied, nodamage to the respiratory tract was observed. It is surprising that thedoxorubicin was not toxic to the lung when given by inhalation atclinically relevant doses such as 20 to 60 mg/m². Unlike 5-FU and Ara-C,and cisplatin, doxorubicin is well known to generate the production offree radicals (Myers et al, 1977) which are notorious for causingpulmonary toxicity (Knight, 1995). It is this property, in fact, whichis held responsible for the cardiotoxicity caused by doxorubicin givenby the intravenous route (Myers et al, 1977).

In some typical embodiments, to obtain additional benefits of thedisclosed invention for treating pulmonary neoplasms and reducingsystemic toxicity, it is important that antineoplastic drugsadministered in non-encapsulated form by the pulmonary route be absorbedinto and remain in the tumor tissue for an extended period of time anddiffuse across the lung mucosa in a relatively slow manner. In general,although solubility, charge and shape have an influence, slow diffusionis obtained by drugs having higher molecular weights while fasterdiffusion is obtained by those having relatively lower molecularweights. Thus drugs such as doxorubicin having a molecular weight of543.5, have relatively slow rates of diffusion, drugs such asvincristine (MW=825), vinblastine (MW=811), paclitaxel (MW=854),etoposide (MW=589), having higher molecular weights also diffuse slowly.Other drugs having somewhat lower molecular weights such as9-aminocamptothecin, while diffusing more slowly are still includedwithin the invention. It has been demonstrated that significantly highertissue concentrations can be achieved in the lung by pulmonary deliverycompared to conventional parenteral or oral administration. Further,systemic coverage of micrometasteses can be provided under theseconditions, with the benefit of significantly greater doses of drugdelivered to the respiratory tract tumor sites and controlled systemicexposure.

Thus in one embodiment of the invention drugs having a molecular weightabove 350 are used. In this regard mitomycin-C (MW of about 334) is thusexcluded from this embodiment. While molecular weight is not the soledeterminant controlling diffusion through the lung it is one of theimportant factors for selecting compounds useful in the presentinvention. This lower molecular weight limit is about 64% that ofdoxorubicin. This will help assure that the limited systemicavailability of the drug discussed above is maintained. In furtherembodiments of the invention the molecular weight of the drugsadministered is above 400, 450, and 500 respectively.

In conjunction with the above discussed molecular weights, proteinbinding of the antineoplastic agents to be delivered by pulmonaryadministration should also be considered with respect to diffusionthrough the lung. Higher rates of protein binding will further slowdiffusion through the lung mucosa. In this respect 5-FU and Ara-C inaddition to having low molecular weights also have relatively lowprotein binding affinity of 7% and 13% respectively. That is, whenplaced into a protein-containing solution, only 7% and 13% of thesedrugs bind to the protein while the remainder is free in solution. Inthis respect, cisplatin does not bind to tissues, rather at a laterstage it is the platinum in the cisplatin that binds to tissues, thusallowing cisplatin to enter systemic circulation as further discussedbelow. In comparison doxorubicin, vincristine, vinblastine, paclitaxel,etoposide, and 9-amino-camptothecin have rates of protein binding above50%. Typically protein-binding affinity above 25% is preferred, morepreferred is binding above 50%, with protein binding above 75% beingmost preferred when lung retention is the objective.

In a preferred formulation and method for treating neoplasms of thepulmonary system by inhalation, the diffusion characteristics of theparticular drug formulation through the pulmonary tissues are chosen toobtain an efficacious concentration and an efficacious residence time inthe tissue to be treated. Doses may be escalated or reduced or givenmore or less frequently to achieve selected blood levels. Additionallythe timing of administration and amount of the formulation is preferablycontrolled to optimize the therapeutic effects of the administeredformulation on the tissue to be treated and/or titrate to a specificblood level.

Diffusion through the pulmonary tissues can additionally be modified byvarious excipients that can be added to the formulation to slow oraccelerate the absorption of drugs into the pulmonary tissues. Forexample, the drug may be combined with surfactants such as thephospholipids, dimyristoylphosphatidyl choline, anddimyristoylphosphatidyl glycerol. The drugs may also be used inconjunction with bronchodilators that can relax the bronchial airwaysand allow easier entry of the antineoplastic drug to the lung. Albuterolis an example of the latter with many others known in the art. Further,the drug may complexed with biocompatible polymers, micelle formingstructures or cyclodextrins.

Particle size for the aerosolized drug used in the present examples wasmeasured at about 2.0-2.5 μm with a geometric standard deviation (GSD)of about 1.9-2.0. Typically the particles should have a particle size offrom about 1.0-5.0 μm with a GSD less than about 2.0 for depositionwithin the central and peripheral compartments of the lung. As notedelsewhere herein particle sizes are selected depending on the site ofdesired deposition of the drug particles within the respiratory tract.

Aerosols useful in the invention include aqueous vehicles such as wateror saline with or without ethanol and may contain preservatives orantimicrobial agents such as benzalkonium chloride, paraben, and thelike, and/or stabilizing agents such as polyethyleneglycol.

Powders useful in the invention include formulations of the neat drug orformulations of the drug combined with excipients or carriers such asmannitol, lactose, or other sugars. The powders used herein areeffectively suspended in a carrier gas for administration.Alternatively, the powder may be dispersed in a chamber containing a gasor gas mixture which is then inhaled by the patient.

Further, the invention includes controlling deposition patterns andtotal dose through careful control of patient inspiratory flow andvolume. This may be accomplished using the pulmonary devices describedherein and similar devices. The inventors have shown by gammascintigraphy measurements that drug aerosol deposition is maximized andevenly distributed in the peripheral lung when the patient inhales usingslow flow rates and inhales to maximum lung volumes followed by briefbreath holds. Central lung deposition is favored when faster inspiratoryflow rates and lower inspiratory volumes are used. Further, totaldeposited and regionally deposited doses are significantly changed as apatient's inspiratory patterns change. Therefore, the method oftreatment and the use of the delivery devices described herein can bemodified to target different regions of the respiratory tract andadjusted too deliver different doses of drug. It is the integration ofdrug molecular weight, protein binding affinity, formulation, aerosolgeneration condition, particle sized distribution, interface of aerosoldelivery to the patient via the device and the control of the patient'sinspiratory patterns that permit targeted and controlled delivery ofhighly toxic anti-cancer drugs to the respiratory tract with the optionto minimize or provide controlled systemic availability of drug.

EXAMPLE 4

The tests for administration of doxorubicin by inhalation referred to inExample 3 were substantially repeated at different dosages using adifferent drug administration system 500 described below. In the presentexamples eight dogs were used. The dogs were divided into two dosegroups. A first group was the low dose group given a total daily dose of60 mg/m² for three days or a total dose of 180 mg/m². This resulted in apulmonary deposition of about 90 mg/m².

A high dose group was administered a dose of 180 mg/m² daily for threedays or a total dose of 540 mg/m². This resulted in a pulmonarydeposition of about 270 mg/m².

One half of the animals were necropsied after three days of exposure andthe remaining dogs necropsied after a three day recovery period.

The purpose of the tests was to identify the maximum tolerated dose ofinhaled drug.

For comparison with the results of Examples 2 and 3, one can convert thedata from mg/kg to mg/m² (m² of body area) by multiplying by 20(conversion factor for the dog). Thus the exposure of the dogs inExamples 2 and 3 which were the equivalent of a clinical dose (for dogs)was about 20 mg/m². When one compares these dosages to those of Example4 (180 mg/m² and 540 mg/m²) it is apparent that a significantly higherdose of non-encapsulated drug can be delivered to the lung compared tothe known art. Although dogs receiving the lower total dose rangesshowed few toxic effects, while dogs receiving the higher total doseshad pulmonary toxicity, these doses were 9-27 times higher than thosegenerally given clinically to dogs.

While the present examples used active drug doses of doxorubicin ofabout 20 mg/m², 180 mg/m², and 270 mg/m², effective amounts of theactive anticancer drugs can be from very small amounts to those wheretoxicity to normal tissue becomes a problem. As used herein, effectiveamounts and pharmaceutically effective amounts of antineoplastic drugdeposited or applied to areas needing treatment are dosages that reducea neoplasm or tumor mass, stop its growth or eliminate it altogether.

Referring now to FIG. 5, the liquid formulation was administered to thedogs by aerosolizing with a nebulizer exposure system 500 comprising aPari LC Jet Plus™ nebulizer 501. The nebulizer was filled with thesolution of drug with which the dogs were to be treated. The output ofthe nebulizer 501 was pulsed in a series of bursts over time (one pulseevery ten seconds). The nebulizer 501 was attached directly to a 460 ccvolume plenum 503 and the plenum 503 was connected to a canine mouthonly exposure mask 415 via a short piece of anesthesia tubing 505 andY-fitting 507. The mask 415 was tapered to approximately fit the shapeof the dog's snout. There was no bias airflow through the exposuresystem 500. The test atmosphere was pulled through the exposure system500 by the inhalation of the dog 511. A one way breathing valve 513 onthe top of the nebulizer 501 allowed the dog 511 to draw in room air andpull the air through the system 500. The air entrained and transportedthe aerosolized drug through the plenum 503, tubing 505, Y-fitting 507,and mask 415 to the dog 511. A one way valve 515 connected to theY-fitting 507 allowed the dog 511 to exhale and the exhaled air exitedthe system. An air supply 520 provided a flow of air to controller 530via line 521. Air flow to the nebulizer was controlled by controller 530and supplied to the nebulizer via line 531.

Referring now to FIG. 6, details of mask 415 are shown. Means forenclosing the mouth and nose are of flexible material and are preferablyheld on by straps such as Velcro™ straps or belts. Means for enclosing601 has one end 603 for inserting the nose and mouth of the dog whilethe other end 605 has two openings 607,609 for attachment of nose outlettube 611. Nose outlet tube 611 has a one way valve 613 that allows thedog to exhale but not inhale through the its nose. Mouth tube 621 isinserted and attached to opening 609 and lies within the means forenclosing 601. An optional Y-connector 623 may be attached and used withmouth tube 621 for providing and receiving inhaled and exhaled gases.Air is generally inhaled through leg 625 of the Y-connector 623. The airpasses through the mouth tube 621 and out the inner opening 631 into therespiratory system of the dog. Inner opening 631 is cut at an angle withits lower portion 633 extending further into the mouth of the dog thanthe upper portion 635. Lower portion 633 functions to depress the tongueof the dog and allow more efficient flow of air and aerosol into thedog. When the dog is wearing mask 415 it can only breathe in through itsmouth using the mouth tube 621. Means for enclosing 601 effectivelyseals the dog's mouth and nose from outside air. The use of a noseoutlet tube 611 has been found to greatly ease the dogs wearing of themask. Air exhaled through the mouth exits mouth tube 621 and passes intooptionally attached Y-connector or to another tube not shown. Air exitsY connector 623 via outlet tube 627. If desired the Y-connector 623 orother outer tube (e.g. straight tubing) may be made of one piece andsimply pass into the enclosing means 601 or may be of separate piecesthat fit together. In either case an adapter 637 may be used to hold themouth tube 621 and or other tubing to which it is connected.

A general device for administering aerosols to a patient includes aninhalation mask for administering aerosols to the including means forenclosing the mouth and nose of the patient, having an open end and aclosed end, the open end adapted for placing over the mouth and nose ofthe patient; upper and lower holes in the closed end adapted forinsertion of a nose outlet tube and a mouth inhalation tube; the noseoutlet tube attached to the upper hole, adapted to accept exhaled breathfrom the nose of the patient; a one way valve in the nose tube adaptedto allow exhalation but not inhalation; the mouth inhalation tube havingan outer and an inner end, partially inserted through the lower hole,the inner end continuing to end at the rear of the patients mouth, theinhalation tube end cut at an angle so that the lower portion extendsfurther into the patients mouth than the upper portion and adapted tofit the curvature of the rear of the mouth; and a y-adapter attached tothe outer end of the mouth inhalation tube.

Pulmonary administration by inhalation may be accomplished by means ofproducing liquid or powdered aerosols, for example, by the devicesdisclosed herein or by using any of various devices known in the art.(see e.g. Newman, S. P., 1984, in Aerosols and the Lung, Clarke andDavia (Eds.), Butterworths, London, England, pp. 197-224; PCTPublication No. WO 92/16192 dated Oct. 1, 1992; PCT Publication No. WO91/08760 dated Jun. 27, 1991; NTIS Patent Application 7-504-047 filedApr. 3, 1990 by Roosdorp and Crystal) including but not limited tonebulizers, metered dose inhalers, and powder inhalers. Various deliverydevices are commercially available and can be employed, e.g. Ultraventnebulizer (Mallinckrodt, Inc, St. Louis, Mo.); Acorn II nebulizer(Marquest Medical Products, Englewood, Colo.); Ventolin metered doseinhalers (Glaxo Inc., Research Triangle Park, N.C.); Spinhaler powderinhaler (Fisons Corp., Bedford, Mass.) or Turbohaler (Astra). Suchdevices typically entail the use of formulations suitable for dispensingfrom such a device, in which a propellant material may be present.Ultrasonic nebulizers may also be used.

Nebulizer devices such as those in Greenspan et al U.S. Pat. Nos.5,511,726 and 5,115,971 are useful in the invention. These devices useelectrohydrodynamic forces to produce a finely divided aerosol havinguniformly sized droplets by electrical atomization. While the Greenspandevices use piezoelectric materials to generate electrical power anypower source is acceptable to produce the electrohydrodynamic forces fornebulization.

A nebulizer may be used to produce aerosol particles, or any of variousphysiologically inert gases may be used as an aerosolizing agent. Othercomponents such as physiologically acceptable surfactants (e.g.glycerides), excipients (e.g. lactose), carriers (e.g. water, alcohol),and diluents may also be included.

As will be understood by those skilled in the art of deliveringpharmaceuticals by the pulmonary route, a major criteria for theselection of a particular device for producing an aerosol is the size ofthe resultant aerosol particles. Smaller particles are needed if thedrug particles are mainly or only intended to be delivered to theperipheral lung, i.e. the alveoli (e.g. 0.1-3 μm), while larger drugparticles are needed (e.g. 3-10 μm) if delivery is only or mainly to thecentral pulmonary system such as the upper bronchi. Impact of particlesizes on the site of deposition within the respiratory tract isgenerally known to those skilled in the art. See for example thediscussions and figures in the articles by Cuddihy et al (AerosolScience; Vol. 4; 1973, pp 35-45) (FIGS. 6, 7, and 8 of the article) andThe Task Group on Lung Dynamics (FIG. 11 and 14 of the article). As aresult primary cancers in the naso-pharyngial or oral-pharyngeal regionsand upper tracheo-bronchial regions, often referred to as cancers of thehead and neck, are treatable with the present invention. The majormetastatic sites (lung and upper respiratory tract) are also readilytreated with this invention simultaneously, unlike current methods oftreatment.

Referring now to FIG. 7, there is disclosed a nebulizer apparatus 700that is preferably portable for administration of drug to a patient inneed of therapy. The nebulizer apparatus 700 is used in combination withthe highly toxic drugs of the present invention and with drugs havingproperties adapted for optimum treatment of neoplasms as discussedelsewhere herein. FIG. 7 is a schematic of a nebulizer combinationaccording to the present invention. Nebulizer 701 may be any nebulizeras described earlier herein that is able to produce the particle sizesneeded for treatment. In combination with nebulizer 701 there isprovided a highly toxic drug formulation 703 for treatment of neoplasmsas disclosed herein. An air supply 705 is provided either as a tank ofcompressed gas or as a motorized pump or fan for moving air from theroom. An optional mouthpiece 707 may be used where it is necessary toprovide sealed contact between the nebulizer and the patient. Optionallythe mouthpiece 707 may be molded as part of nebulizer 701. Power for useof the nebulizer apparatus 700 may come from the compressed gas fromhand manipulation by the user or administrator or by batteries orelectrical power not shown but well known by those skilled in the art.

To control environmental contamination resulting from use of anebulizer, the patient may be placed in a well-ventilated area withexhaust air filtered to remove antineoplastic drug that escapes from thedevice.

EXAMPLES 5 to 11

Examples 5F to 11F show inhalation feasibility and proof of concepttests and Examples 5R to 10R show dose escalation range tests with:vesicant antineoplastic drugs including doxorubicin, paclitaxel,vincristine, vinorelbine; nonvesicant drugs including etoposide, and9-aminocampothecin (9-AC) and carboplatin. The drugs were delivered tothe pulmonary system via aerosol at a particle size of about 2 to about3 μm. The drugs were delivered in water or other vehicles appropriatefor the drug as is known in the art and as exemplified herein.

Table 7 illustrates the dosage schedule for the range-finding studies. Aminimum of 7-14 days separated each escalating dose. No range findingtests, only feasibility tests, were performed for mitomycin-C and 9-AC.No feasibility tests, only dose range-finding tests, were performed forvinorelbine. It is important to note that the doses listed in Table 7are the pulmonary deposited doses not the total doses administered.

The results of the feasibility and dose escalation studies aresummarized in Tables 7 to 11.

TABLE 7 Escalating Dose Regimen for Range-Finding Studies Mean PulmonaryDeposited Dose Example 1^(st)Dose 2^(nd)Dose 3^(rd)Dose 4^(th)Dose5^(th)Dose 6^(th)Dose No. Test Drug (mg) (mg) (mg) (mg) (mg) (mg) 5RPaclitaxel 30 35 40 40 60 — 6R Doxorubicin 12 15 15 15 18 — 7RVincristine 0.55 0.55 0.70 0.70 1.1 1.5 8R Vinorelbine 6 10 10 15 15 —9R Etoposide 25 30 45 55 40 80 10R  9-AC — — — — — 11R  Carboplatin 30 —— — — Notes: A minimum of 7-14 days separated each escalating dose.Animals necropsied after last dosing

Animals used in Examples 5 to 11 were adult beagle dogs. For thefeasibility studies, the dogs were initially given a single intravenous(IV) dose of antineoplastic drug. This dose was given to allow acomparison of how much drug was absorbed into the blood after inhalationcompared to IV delivery. The IV dose given was typically the usual humanclinical dose that had been scaled down for the dogs based ondifferences in body mass, or the maximum tolerated dose in the dog,whichever is greater. An average human having a weight of 70 kg isconsidered to have a weight to body surface ratio of 37 kg/m² and a lungsurface area of 70-100 m² of lung surface area. The average dog used inthe tests was considered to have a weight of 10 kg corresponding and aweight to body surface ratio of 20 kg/m² and a lung surface area of40-50 m² lung surface area (CRC Handbook of Toxicology, 1995, CRC PressInc.). The single IV dose was used to quantify the plasma kinetics. Withmost of the cytotoxic agents treated, the single IV dose resulted in apredictable mild decrease in white blood cell counts, with no othermeasurable toxicities.

After the initial IV and before the inhalation feasibility tests, thedogs were allowed a washout period of at least seven days (until thedogs returned to normal conditions) before they were treated withinhaled antineoplastic drugs. In the inhalation feasibility tests thedogs were generally exposed to a dose of inhaled antineoplastic drug inaerosol form once per day for three consecutive days (except as noted inTables 8 to 11) and necropsied one day following the last dose with theplasma kinetics characterized after the first and third exposures. Withthe exception of cisplatin and the high dose of doxorubicin, whichcaused toxicity to the respiratory tract, the drugs did not exhibit anysignificant pulmonary toxicity in these repeated exposure inhalationfeasibility studies. In the feasibility tests the dogs used the samemask and apparatus used for the earlier examples. In the doserange-finding tests, in order to control the deposited dose, the dogswere fitted with an endo-tracheal tube and the drug administered as anaerosol directly from the endo-tracheal tube. This latter procedure madeit easier to control the pulmonary deposited dose since the aerosol wasreleased directly into the pulmonary air passages assuring deepdeposition of the drug in the lung. Also use of the endo-tracheal tubemade it possible to do the tests in a shorter time since the dogs neededa four to six week training period to properly acclimate to and use themasks. The calculated deposited doses obtained herein were verifiedexperimentally by pulmonary scintigraphy tests in dogs.

EXAMPLES 5F and 5R

Referring now to Table 8, this table shows the details of thefeasibility test of paclitaxel. Initially the dogs were administered 120mg/m² of paclitaxel by IV. After the washout period the dogs wereadministered a total deposited dose of 120 mg/m² of paclitaxel, byinhalation, three times for a total deposited dose of 360 mg/m². Thisadministered dose resulted in a pulmonary deposited dose of about 27 mgeach time or a total pulmonary dose of about 81 mg. This represents atotal pulmonary deposited dose of about 2.1 mg/m² of lung surface area.The dosages were calculated as follows: the dose of 120 mg/m² wasdivided by 20 kg/m² to yield a 6 mg/kg dose that was multiplied by 10 kgfor the average dog to yield about 60 mg of drug. Since the dogs wereusing the masks for drug administration, one half or about 30 mg of drugwas considered deposited in the deep lung. Since the drug wasadministered three times the total drug exposure was about 90 mg. The 90mg of drug was divided by 40 to yield a total dose to the lung of about2.25 mg/m² lung surface area.

The clinical condition of the dogs was normal. Clinical pathologyprofiles were normal with only mildly reduced white blood cell counts.The histopathology showed bone marrow and lymphoid depletion, GI villousatrophy and congestion and laryngeal inflammation. These changesindicated that some significant fraction of the deposited drug wasabsorbed systemically. There was no respiratory tract toxicity found.Bioavailability of the paclitaxel was found to be low to moderate basedon plasma kinetic evaluations. The low to moderate bioavailabilityindicates that most of the paclitaxel remained in the lungs and did notrapidly enter systemic circulation in large amounts. Therefore, giventhe lack of significant direct respiratory tact toxicity, the probabledose limiting toxicity is considered to be myelosuppression and/or GItoxicity. Thus factors extrinsic to the lung are expected to limitdosages provided by the pulmonary route.

Referring again to Tables 7 and 8, in the range-finding tests 60 to 120mg/m² of paclitaxel were administered at weekly intervals for fiveweeks. The amount of pulmonary deposited dose ranged from about 30 toabout 60 mg. This range corresponded to about 0.75 to about 1.50 mg/m²lung surface area. The clinical conditions of these dogs were normal,with clinical pathology changes limited to moderate white blood cellcount reduction. The histopathology showed thoracic and mesentericlymphoid depletion along with GI inflammation and ulceration. Thehistopathology reflects that normally found in IV administration ofpaclitaxel particularly GI inflammation and ulceration which is probablyassociated with systemically administered paclitaxel. Respiratory tracttoxicity indicated minimal pulmonary interstitial inflammation. Systemicbioavailability was proportional to dose. The probable dose limitingtoxicity is myelosuppression and GI toxicity, and not pulmonarytoxicity.

TABLE 8 Paclitaxel Summary Results of Dog Feasibility and DoseRange-Finding Studies Probable Pulmonary Respiratory Dose- Chemo- IVInhalation Deposited Clinical Clinical Tract Limiting therapy dose DoseDose Condition Pathology Histopathology Toxicity BioavailabilityToxicity Example 5F 120 120 30 mg × 3 Normal ↓ WBC Bone marrow NoneLow-moderate Myelo- Paclitaxel mg/m² mg/m² × 3 doses & lymphoidsuppression Feasibility (360 depletion GI mg/m² GI villous toxicitytotal) Atrophy & congestion Laryngeal inflammation Example 5R NA 60-12030-60 mg Normal ↓↓ WBC Thoracic and Minimal Proportional Myelo-Paclitaxel mg/m² (5 per dose mesenteric pulmonary to dose suppressionDose Range- wkly Rx) lymphoid interstitial GI Finding depletioninflamma- toxicity GI tion inflammation and ulceration * - Divide thepulmonary deposited dose in mg by 40 to get the pulmonary deposited dosein mg/m² of lung surface area. WBC - white blood cell count

EXAMPLES 6F and 6R

Referring now to Table 9, 20 mg of doxorubicin were initiallyadministered by IV. After the washout period three sets of inhalationfeasibility tests were made. In the first, a single dose of 20 mg/m² ofdoxorubicin was administered that gave about a 10 mg body dose, apulmonary deposited dose of about 5 mg or about 0.125 mg/m² lung surfacearea. No changes were noted in the animal from this dose. A second setof moderate inhalation dosages of about 40 mg/m² of doxorubicin (about10 mg deposited within the lung) was administered three times a day forthree consecutive days. Total cumulative dose administered was 120 mg/m²corresponding to a about a 60 mg body dose, and a total pulmonarydeposited dose of about 30 mg (or about 0.75 mg/m² of lung surfacearea). A third set of high inhalation dosages of 120 mg/m² ofdoxorubicin was administered three times per day over a three day periodfor a total dose of 360 mg/m² corresponding to a 180 mg body dose, atotal pulmonary deposited dose of about 90 mg or about 2.25 mg/m² oflung surface area. One half of the low dose group dogs was necropsiedthe day after the final exposure and the remaining half was necropsiedfour days later. All high dose dogs were necropsied the day after thefinal exposure.

Exposure to these extremely high doses resulted in the death of one highdose group dog after three days of exposure with the remaining threedogs euthanized in moderately debilitated to moribund conditions. Thisdose intensive treatment caused pulmonary edema, a sequela ofmicroscopically recognizable degeneration, necrosis and inflammation ofepithelial surfaces lining the bronchials and larynx and the mucosalsurfaces of the nose and lips. These lesions were life threatening andmore severe in the high dose group, but were considered survivable atthe lower dose, based on the clinical condition of the animals. Despitethese higher doses, there were no clinical pathology changes indicativeof doxorubicin induced myelosuppression. There was microscopic evidenceof lymphoid depletion in the regional lymph nodes of the respiratory andgastrointestinal tracts suggestive of regional drainage of freedoxorubicin to the draining lymph nodes of the thoracic and GI systems.WBC values actually increased in the high dose group, a changeassociated with the inflammatory response observed in the respiratorytract. There were no other clinical pathology changes of note other thanincreased serum alkaline phosphatase in the high dose group, anonspecific change, due likely to respiratory tract tissue damage.

Generally, changes noted at the moderate and high dosages were edema,increased white blood cell count and increased respiratory rate.Histopathology revealed thoracic and GI lymphoid depletion for themoderate and higher doses, respectively. Respiratory tract toxicityincluding airway epithelial degeneration and moderate to severeinflammation was noted at the increased dosages. Bioavailability was lowto moderate indicating an absorption rate limiting process in movementof the drug into the systemic circulation. The probable dose limitingtoxicity of doxorubicin is expected to be respiratory tract toxicityrather than a systemic toxicity.

In addition, a dose escalation study was conducted on a weekly exposureschedule. Initial doses of 12 mg deposited were delivered viaendotracheal tube to the lungs, with a 5^(th) weekly dose of 18 mgdeposited within the lungs. This provided a total body dose of 24 to 36mg/m². The results of this repeated dose trial were similar in character(but not in severity) to the higher dose tests. Animals survived thistreatment regimen with minimal clinical evidence of toxicity and noevidence of systemic changes. Histologically, there was no evidence ofrespiratory tract epithelial degeneration and inflammation.

TABLE 9 Doxorubicin Summary Results of Dog Feasibility and DoseRange-Finding Studies Probable Pulmonary Respiratory Dose- Chemo- IVInhalation Deposited Clinical Clinical Tract Limiting therapy dose DoseDose* Condition Pathology Histopathology Toxicity BioavailabilityToxicity Example 6F 20 20 mg/m² × 5 mg No change No change No change Nochange Low-moderate Respiratory Doxorubicin mg/m² 1 (absorption tracttoxicity Feasibility 40 mg/m² × 10 mg × 3 Mild- ↑ WBC Airway ratelimited) 3 doses doses moderate Thoracic & GI epithelial (120 pulmonaryLymphoid degenera- mg/m² edema depletion tion total) ↑IRR 120 mg/m² × 30mg × 3 Marked ↑↑ WBC Thoracic & GI Moderate- 3 doses doses edemaLymphoid severe (360 ↑↑IRR depletion inflamma- mg/m² tion total) Example6R N/A 24-36 12-18 mg ↑IRR ↓ WBC Mild-moderate Mild- Low-moderateRespiratory mg/m² per dose thoracic and moderate tract toxicityDoxorubicin (5 wkly Rx) Mild mesenteric degenera- Dose Range- transientlymphoid tion of Finding pulmonary depletion airway edema epitheliumMild- moderate interstitial inflam. ↑ - Increase ↓ - Decrease IRR -increased respiratory rate WBC - white blood cells *Divide the pulmonarydeposited dose in mg by 40 to get the pulmonary deposited dose in mg/m²of lung surface area.

Plasma levels of doxorubicin were dose dependent and exhibited clearevidence of drug accumulation, including daily increases in Cmax(maximum concentration in blood) and steady state-like profiles,suggesting there was a rate limited absorption from the lung into theblood with significant accumulation of doxorubicin in the lungsfollowing each additional exposure given at a frequency of dailyintervals. This accumulation was considered likely responsible for thetissue damage observed.

Referring again to Tables 7 and 9, an inhalation dose range of 20-40mg/m² was administered in five weekly doses that resulted in a bodyexposure of about 10 mg to about 20 mg, a pulmonary deposited dose rangeof about 10 to about 20 mg or a range of about 0.25 mg/m² to about 0.5mg/m² lung surface area. The clinical condition included increasedrespiratory rate and mild transient pulmonary edema. A decrease in whiteblood cell count was noted for the higher dosages. Histopathologyrevealed mild to moderate thoracic and mesenteric lymphoid depletion.Respiratory tract toxicity noted was mild to moderate degeneration ofairway epithelium. A mild to moderate to marked interstitialinflammation was noted with some limited fibrosis. Bioavailability wasnoted to be low to moderate with absorption being rate limited. Theprobable dose limiting toxicity appears again to be respiratory tracttoxicity.

EXAMPLE 7F and 7R

Referring now to Table 10, 1.4 mg of vincristine was initiallyadministered by IV. After the washout period one inhalation feasibilitytest was made. The vincristine was formulated in a 50% water/ 50%ethanol vehicle. A single dose of 2.8 mg/m² of vincristine wasadministered that gave about a 1.8 mg body dose, a pulmonary depositeddose of about 0.9 mg or about 2.25 mg/m² lung surface area. No changeswere noted in the animal from this dose.

TABLE 10 Vincristine & Vinorelbine Summary Results of Dog Feasibilityand Dose Range-Finding Studies Probable Pulmonary Respiratory Dose-Chemo- IV Inhalation Deposited Clinical Clinical Tract Limiting therapydose Dose Dose Condition Pathology Histopathology ToxicityBioavailability Toxicity Example 7F 1.4 2.8 mg/m² × 0.7 mg Normal NormalNo change No change Undetermined Undeter- Vincristine mg/m² 1 minedFeasibility Example 7R N/A 1.1-3.0 0.55-1.5 Normal ↓ WBC Minimal-mildMinimal Undetermined Myelosup- Vincristine mg/m² (6 mg/dose bone marrowinterstitial pression Dose Range- wkly Rx) and lymphoid inflammationFinding depletion Example 7R N/A 12-30 6-15 mg Normal ↓ WBC Bone marrowMinimal Undetermined Myelo- Vinorelbine mg/m² (5 per dose and lymphoidpulmonary suppression Dose Range- wkly Rx) depletion and airway Findinginflam. ↑ - Increase ↓ - decrease IRR - increased respiratory rate WBC -white blood cell * - Divide the pulmonary deposited dose in mg by 40 toget the pulmonary deposited dose in mg/m² of lung surface area.

Referring now to Tables 7 and 10, range finding tests of inhaledvincristine were made in the range of 0.5 to 1.5 mg of pulmonarydeposited vincristine administered in six weekly doses. Therefore theamount of pulmonary deposited dose ranged from about 12.5-37.5 μg/m²lung surface area. This corresponded to a total body dose of 50-150μg/kg or 1.0-3.0 mg/m² of body surface area. This dose range is near andgenerally above typical dose ranges for vincristine given IV. But in theexamples given here, the entire dose was administered to the lungs.Vincristine is a potent drug and causes significant myelosuppression andneurotoxicity at doses above 1.0 mg/m² given systemically. The resultsof the pilot inhalation studies showed the drug was well tolerated atall doses delivered by pulmonary administration with little to noevidence of respiratory tract toxicity with mild lymphoiddepletion/myelosuppression only occurring at the highest doses given(2.0-3.0 mg/m²).

EXAMPLE 8R

Vinorelbine, which is also a vinca alkaloid was evaluated in a repeatedexposure pilot tests. Compared to vincristine, vinorelbine wasapproximately 5-10 times less potent in producing toxicity, but producedsimilar types of changes. Vinorelbine delivered by pulmonaryadministration directly into the lungs of dogs by endotracheal tube, ona weekly basis (for 5 weeks) at escalating doses was well tolerated. Adose of 6 mg deposited in the lung was initially selected and escalatedto 15 mg deposited within the lung. This represented a lung surfaceexposure of ˜0.15-0.375 mg/m² of lung surface area and total body dosesof 12-30 mg/m². This treatment regimen produced very minimal effectswithin the respiratory tract, characterized principally by slightinflammation. At the higher dose levels, inhaled vinorelbine producedsufficient blood levels to cause mild to moderate myelosuppression andlymphoid depletion, both of which were reversible and of a severity,which was not life-threatening.

EXAMPLES 9F and 9R

An additional proof of concept, pilot inhalation tests involvedetoposide. Etoposide is a cytotoxic drug, representative of a class ofdrugs known as topoisomerase II inhibitors. Given orally or IV,etoposide causes typical cytotoxic systemic toxicity, includingmyelosuppression, severe GI toxicity and alopecia. Etoposide is a highlyinsoluble drug and therefore difficult to formulate. The vehicle usedclinically also causes adverse effects, predominantly anaphylactic typereactions.

In this invention, etoposide was reformulated in a novel vehicle,dimethylacetamide (DMA) which does not cause anaphylactic reactions.While DMA cannot be used for IV administration due to systemic toxicity,it was shown to be a safe delivery vehicle for the pulmonary route ofdelivery. The etoposide was delivered in a 100% DMA vehicle. Thisformulation allowed the formation of the appropriate particle sizes. Inthese tests, escalating doses of etoposide were given to dogs on aweekly schedule. The initial dose used was 25 mg of etoposide depositedin the pulmonary region with a 6^(th) and final dose delivered of 80 mgdeposited within the pulmonary region. This equated to a dose range of50-160 mg/m² of body surface area. This treatment regimen caused nosystemic toxicity and only minimal inflammation of the lung and no overtdamage of the respiratory tract. In addition, there was good evidence oflymphoid depletion of the thoracic lymph nodes, in the absence ofsystemic changes, indicating that the drug was draining directly throughthe regional lymph system. This would provide additional regionaltherapeutic effectiveness in dealing with metastatic cells.

An additional pharmacokinetic test of inhaled etoposide showed the drughad moderately good bioavailability. A single inhaled total depositeddose of 260 mg/m² (about 65 mg of drug deposited in the pulmonaryregion) produced blood levels of etoposide similar to an IV dose of 50mg/m² (see FIGS. 1-3). In other words, to reach similar bloodconcentrations approximately 5× more drug was given by inhalation, adose which caused neither respiratory tract nor systemic toxicity.

EXAMPLE 10F

Additional proof of concept inhalation studies involved the cytotoxicdrug 9-aminocamptothecin (9-AC) which is within the drug class known ascamptothecins. Like etoposide, 9-AC is insoluble and difficult toformulate. Supporting the concept and claims of this invention, theinventors generated aerosols of 9-AC formulated as a microsuspension inan aqueous vehicle (100% water).

These aerosols were delivered to dogs at daily doses of 40 mg/m² bodysurface area (10 mg of drug deposited within the pulmonary region) for 3consecutive days. Inhalation treatment produced lower drug plasma levelsthan an IV dose of 10 mg/m². The daily inhalation dose was 4 timesgreater than the IV dose and the total cumulative 3 day inhalation dosewas 12 times greater than the single IV dose given (which causes mildsystemic toxicity). Despite the significantly greater doses given byinhalation, there were no measurable toxic effects (neither localeffects within the respiratory tract nor systemic changes). Results fromthese tests supported the concept of improved overall safety anddose-intensification within the respiratory tract and also demonstratedthe concept with aerosolized microsuspensions of chemotherapeutic drugs.

EXAMPLE 11F

In addition, this feasibility trial was extended to examine anotherplatinum-containing chemotherapeutic, carboplatin. The usual clinicalformulation using water was used. Carboplatin is generally consideredless toxic than cisplatin at comparable doses, and this appearedconsistent with the results seen when the two agents were delivered byinhalation. Inhaled doses of up to 30 mg carboplatin deposited viaendotracheal tube into the lungs of dogs (60 mg/m² total body dose)caused no evidence of either direct respiratory tract or systemictoxicity.

TABLE 11 Etoposide, & 9-Aminocampothecin (9-AC) Summary Results of DogFeasibility and Dose Range-Finding Studies Probable PulmonaryRespiratory Dose- Chemo- IV Inhalation Deposited Clinical Clinical TractLimiting therapy dose Dose Dose* Condition Pathology HistopathologyToxicity Bioavailability Toxicity Example 9F 50 260 mg/m² × 65 mg × 3Normal No change Mild thoracic None Moderate Undeter- Etoposide mg/m² 3(780 doses lymphoid mined Feasibility mg/m² depletion total dose)Example 9R N/A 50-160 25-80 mg Normal No change Mild-moderate MildModerate Undeter- Etoposide mg/m² (6 dose thoracic interstitial minedDose Range- wkly Rx) lymphoid inflamma- Finding depletion tion Example10F 10 40 mg/m² × 10 mg × 3 Normal No change Minimal MinimalModerate-high Undeter- mg/m² 3 (120 doses lymphoid interstitial mined9-AC mg/m² depletion inflamma- Feasibility total) tion *Divide thepulmonary deposited dose in mg by 40 to get the pulmonary deposited dosein mg/m² of lung surface area.

EXAMPLES 12 to 20

These examples illustrate results of clinical treatment of dogs havingend stage lung cancer where other treatments have failed. For treatment,the dogs were anaesthetized and the inhalation treatment was through anendotracheal tube.

This preliminary trial was performed to determine whether the inhalationchemotherapy treatment could be successfully used in animals with lungtumors. Initially, nine dogs with neoplastic lung disease were studied.Three different drugs were used- doxorubicin, vincristine,cyclophosphamide, cisplatin, and paclitaxel at the doses and schedulessummarized in Table 12.

One 16 year old mixed breed dog had no evidence of tumor in the lungfollowing excision of a primary lung tumor, but did have evidence ofmetastases in the hilar lymph nodes, a sign that metastases would soonappear in the lung. However, the results showed that no metastasesdeveloped in the lung for four months during which time the dog receivedfour treatments of inhaled doxorubicin. In six other dogs, there weremetastases in the lung and in each of these, the inhaled chemotherapystopped the growth of the metastases, i.e. there was stable disease (orSD). In two dogs inhalational chemotherapy was not effective and therewas progressive disease (or PD). Since no chemotherapy was given tothese dogs by the intravenous route, tumors outside of the lungprogressed even while the lung tumors were stabilized. Thus, the resultsdemonstrated that inhalational chemotherapy was effective in the localtreatment of lung cancer in the dog.

TABLE 12 Summary of Preliminary Clinical Results in Dogs Time Dog TypeInhalation of Ex. and Age Diagnosis Treatment* Trial Results 12 AfghanAdvanced Dox 1 week PD 10 years lung 5 mg, × 1 extra- old carcinomapulmonary 13 Cocker Lung Dox 2 mo. SD lung, Spaniel metastasis 5 mg, × 2died 10-12 from excised Vincristine PD extra- years old melanoma 0.5 mg,once pulmonary, died 14 Beagle Thyroid Dox 4 mo. SD lung 7 yearscarcinoma 5 mg, × 4 PD thyroid old with lung & extra- metastasispulmonary, died 15 Labrador Thyroid Dox 2 mo. SD lung 8 years carcinoma5 mg, × 2 PD thyroid old with lung & brain metastasis metastasis, died16 Mixed Excised lung Dox 4 mo. No lung Breed primary, 5 mg, × 4metastasis 16 years positive hilar Death (CNS old lymph nodesmetastasis) 17 Rottweiler Excised Dox 1 mo. PD lung 3 years distal 7 mg,× 2 Further old osteo- Cisplatin Rx declined sarcoma, 15 mg, × 1 lungnodule 18 Mixed Lung (Dox 5 mg + 2-½ mo. SD lung Breed metastasis CTX 25PD visceral 14 years (carcinoma) mg), × 3 & Extra- old Dox pulmonary, 5mg, × 1 died 19 Flat- Excised Paclitaxel 2-½ mo. SD (4 coated salivary22.5 mg, weeks) lung Retriever adeno- QW × 4 PD lung, Rx 8 yearscarcinoma, discontinued old lung metastasis 20 Husky Advanced Paclitaxel2 mo. SD lung 16 years mammary 22.5 mg, × 2 old adeno- (Paclitaxelcarcinoma, 22.5 mg + lung Dox metastasis 5 mg), × 2 *Calculate targetdose. Abbreviations: PD = progressive disease, SD = stable disease; Dox=Doxorubicin; CTX = cyclophosphamide; QW = every week;

EXAMPLES 21 to 33

Additionally, tests were conducted in dogs using a defined protocol. Inthese tests, dogs with either gross metastatic disease, micrometastatichemangiosarcoma or micrometastatic primary lung cancer were randomizedto receive either doxorubicin, paclitaxel or both by inhalation via anendotracheal tube in a crossover design. Aerosol particle size was 2-3μm as in the previous tests. The apparatus used was basically that shownin FIG. 5 and as described above. Formulations for administration of thedrugs were as follows: 16 mg/ml doxorubicin in 70%ethanol/30%water; 75mg paclitaxel in about 30% PEG/70%ethanol. Preferably the paclitaxel isadministered with 0.2% of citric acid to prevent degradation of the drugunless it is immediately used after preparation. The treatments wereadministered once every two weeks, and if a diagnosis of progressivedisease was made on two consecutive intervals the dog was crossed overto the alternate drug. At each treatment session, blood was sampled forhematology and biochemical analyses and urine was collected foranalysis. The status of the tumors was monitored radiographically.

The results are summarized in Table 13. Pulmonary deposited doses listedin the table are based on scintigraphy studies that relate inhaled dosesto deposited doses. Among the 10 dogs that had gross metastatic disease(Examples 21-28), which is regarded as a terminal condition with a veryshort life expectancy, 4 dogs (in Examples 21, 22, 24, and 27) showedstable disease in the lung indicating that the drug was having apositive effect. In the remaining 6 dogs (see Examples 23, 25, 26, and28), the lung disease progressed. In two of the dogs with metastaticosteosarcoma (Examples 24 and 25) and in the dog with metastaticmelanoma (Example 28), there were partial responses, i.e. there weretumors that decreased in size by more than 50%.

Four dogs had splenic hemangiosarcoma (Examples 29 and 30), a diseasethat invariably metastasizes to the lung and is fatal within two to fourmonths. These dogs were given doxorubicin by inhalation in addition tointravenous chemotherapy to control systemic disease. The results inTable 13 show that each of the four dogs was alive (at least two monthsat the time of this writing) and that there was no evidence of diseasein the lung.

The last group of dogs (Examples 31-33) are those that had primary lungtumors which were removed surgically. These dogs had metastases in theirthoracic lymph nodes and have a life expectancy measured in weeks. Asshown in Table 13, two dogs (Examples 31 and 32) received doxorubicin byinhalation (1.5 mg) and two dogs (Example 33) received paclitaxel (20mg). The dog that received five treatments of doxorubicin was alive withno evidence of disease 81 days later suggesting that the treatment ishaving a positive effect. One dog (Example 32) received two doses ofdoxorubicin and died from metastases outside of the lung. The other twodogs (Example 33) have no evidence of disease but not enough time haspassed to determine how effective the treatment will be.

The result of these tests, therefore, confirm those of the preliminarytests that inhalational chemotherapy is effective in the treatment oflung cancer.

TABLE 13 Efficacy of Inhalational Chemotherapy in Dogs with Lung CancerNo. of Inhalation Ex. Diagnosis Dogs Treatment* Results 21 Lungcarcinoma 1 DOX 5 mg (5×) SD then paclitaxel 60 mg (2×) 22 Metastatic 1DOX 5 mg (2×) SD 23 hemangiosarcoma 1 DOX 5 mg (1×) PD 24 Metastatic 1DOX 5 mg (5×) + SD (PR after 3rd osteosarcoma paclitaxel 60 mg DOXtreatment) (2×) 25 Metastatic 3 DOX 5 mg (2×) + PD (PR in one dog)osteosarcoma paclitaxel 60 mg (1×) 26 Metastatic 1 DOX 5 mg (2×) PDfibrosarcoma 27 Metastatic 1 DOX 5 mg (4×) + SD liposarcoma paclitaxel60 mg (1×) 28 Metastatic 1 paclitaxel 60 mg PD (PR noted in melanoma(2×) + nodules < 2 cm) DOX 5 mg (1×) 29 Splenic 2 DOX 5 mg (4×) + Aliveand NED hemangiosarcoma systemic chemotherapy 30 Splenic 2 DOX 1.5 mgAlive and NED hemangiosarcoma (3×) + systemic chemotherapy 31 Primarylung 1 DOX 1.5 mg (5×) Alive and NED tumor 32 excised- 1 DOX 1.5 mg (2×)Dead from extra- micrometastatic pleural metastases 33 disease 2paclitaxel 20 mg Alive and NED (1×) *Deposited pulmonary doses DOX =doxorubicin; (×) = number of treatments received; SD = stable disease;PD = progressive disease; NED = no evidence of disease; PR = partialresponse (50% decrease in tumor size)

The safe and effective range of doses of the inhalant antineoplasticdrugs in humans and animals (e.g. dogs and similar small animals) areshown in Table 14 below. Larger animal dosages can be calculated byusing multiples of the small animal based dose based on the knownrelationship of (body weight in kg/m² of body surface area. The exactdoses will vary depending upon such factors as the type and location ofthe tumor, the age and size of the patient, the physical condition ofthe patient and concomitant therapies that the patient may require. Thedosages shown are for doses for one course of therapy. A course oftherapy may be given, monthly, weekly, biweekly, triweekly or dailydepending on the drug, patient, type of disease, stage of the diseaseand so on. Exemplary safe and effective amounts of carrier are given foreach product have been published by the respective manufacturer and aresummarized in the Physicians Desk Reference.

TABLE 14 Animal Dose* Human Drug mg/m² Dose* mg/m² Doxorubicin   2 to 903 to 130 Paclitaxel   6 to 270 10 to 400  Vincristine 0.06 to 2  0.1 to3    Vinorelbine 1.3 to 60 2 to 90  Cisplatin  4.6 to 200 7 to 300Etoposide  4.6 to 200 7 to 300 9-Aminocampothecin 2.6 to 10 0.04 to15    *m² body surface area

Based on the results of the inhalation tests herein with doxorubicin,inhalation treatments with anthracyclines in addition to doxorubicin arealso expected to be well tolerated and efficacious when administered bythe pulmonary route. Based on the inhalation tests herein withvincristine and vinorelbine, other vinca alkaloids are expected to bewell tolerated and efficacious when administered by the pulmonary route.Based on the inhalation tests herein for the vesicants doxorubicin,vincristine, vinorelbine, and paclitaxel, all of which are capable ofserious vesicating injuries, other vesicating drugs (e.g.mechlorethamine, dactinomycin, mithramycin, bisantrene, amsacrine,epirubicin, daunorubicin, idarubicin, vinblastine, vindesine, and so on)are expected to be well tolerated and efficacious when administered bythe pulmonary route. The exception, of course, would be vesicant drugsthat are known to exhibit significant pulmonary toxicity whenadministered by IV (e.g. mitomycin-C). In this regard, a safe andeffective amount of a particular drug or agent is that amount whichbased on its potency and toxicity, provides the appropriateefficacy/risk balance when administered via pulmonary means in thetreatment of neoplasms. Similarly a safe and effective amount of avehicle or carrier is that amount based on its solubilitycharacteristics, stability, and aerosol forming characteristics, thatprovides the required amount of a drug to the appropriate site in thepulmonary system for treatment of the neoplasm.

For the nonvesicant antineoplastic drugs, based on the inhalation testsherein for the vesicating and nonvesicating drugs it is expected thatall the nonvesicating drugs that do not exhibit direct pulmonarytoxicity when administered intravenously are expected be well toleratedand exhibit efficacy. Bleomycin and mitomycin-C, for example, exhibitsufficient pulmonary toxicity to be excluded except when achemoprotectant is used. In this regard typically carmustine,dacarbazine, melphalan, methotrexate, mercaptopurine, mitoxantrone,esorubicin, teniposide, aclacinomycin, plicamycin, streptozocin,menogaril are expected to be well tolerated and exhibit efficacy.Similarly, drugs of presently unknown classification such asgeldanamycin, bryostatin, suramin, carboxyamido-triazoles such as thosein U.S. Pat. No. 5,565,478, onconase, and SU101 and its activemetabolite SU20 are likewise expected to be well tolerated and exhibitefficacy subject to the limitation on pulmonary toxicity. These drugswould be administered by the same methods disclosed for the testedantineoplastic drugs. They would be formulated with a safe and effectiveamount of a vehicle and administered in amounts and in a dosing schedulesafe and effective for treating the neoplastic disease.

Pulmonary toxicity of compounds to be administered by inhalation is animportant consideration. As mentioned above one of the majorconsiderations is whether the drug exhibits significant pulmonarytoxicity when injected by IV. While almost all antineoplastic drugs aretoxic to the body and thus arguably exhibit pulmonary toxicity if givenin a large enough dose, the test for pulmonary toxicity as used hereinrequires significant pulmonary toxicity at the highest manufacturersrecommended dose that is to be administered to a patient. Thedetermination of whether a drug exhibits sufficient pulmonary toxicityby IV so as to exclude it from the group of drugs useful for pulmonaryadministration can be made from the drug manufacturers recommendationsas published in the Physicians Desk Reference (see “Physicians DeskReference” 1997, (Medical Economics Co.), or later editions thereof), inother drug manuals published for health care providers, publiclyavailable filings of the manufacturer with the FDA, or in literaturedistributed directly by the manufacturers to physicians, hospitals, andthe like. For example in the “Physicians Desk Manual” 1997:

Doxorubicin (Astra) pp. 531-533—vesicant, there is no indication ofpulmonary toxicity while cardiac toxicity, hematologic toxicityparticularly leukopenia and myelosuppression; extravasation injuries arealso noted;

Idarubicin (Pharmacia & Upjohn) pp 2096-2099—vesicant, primary toxicityappears to be myelosuppression no mention is made of pulmonary toxicitymaking the drug useful in the present invention;

Etoposide (Astra) pp539-541—no indication of pulmonary toxicity, butdose limiting hematologic toxicity is important;

Paclitaxel (Bristol-Meyers Squibb) pp. 723-727—vesicant, pulmonarytoxicity is not listed for paclitaxel, but dose limiting bone marrowsuppression (primarily neutropenia) is important;

Bleomycin (Blenoxane® Bristol-Meyers Squibb) pp. 697-699, pulmonarytoxicities occur in about 10% of treated patients by IV administereddrug, this makes bleomycin unacceptable for pulmonary administration forthe present invention;

Mitomycin C (Mutamycin® Bristol-Meyers Squibb)—vesicant, infrequent butsevere life threatening pulmonary toxicity has occurred by IVadministration, this although infrequent severe life threateningpulmonary toxicity shows that the drug exhibits substantial pulmonarytoxicity;

Methotrexate (Immunex) pp. 1322-1327—MW=454, primary toxicity appears tobe hepatic and hematologic, signs of pulmonary toxicity should beclosely monitored for signs of lesions;

Dactinomycin (Merck & Co.)—vesicant, primary toxicity appears to beoral, gastrointestinal, hematologic, and dermologic; no mention is madeof pulmonary toxicity making the drug acceptable in the presentinvention;

mechlorethamine (Merck & Co.)—vesicant, primary toxicity appears to berenal, hepatic and bone marrow, no mention is made of pulmonary toxicitymaking the drug acceptable in the present invention;

Irinotecan (Camptosar® Pharmacia & Upjohn)—a derivative of camptothecin,primary toxicity appears to be severe diarrhea and neutropenia, nomention is made of pulmonary toxicity making the drug useful in thepresent invention;

Vincristine (Oncovin® Lilly) pp. 1521-1523—extremely toxic with highvesicant activity found in the tests herein, but no pulmonary toxicitynoted;

Vinblastine (Velban® Lilly) pp.1537-1540—extremely toxic with highvesicant activity found in the tests herein, but no pulmonary toxicitynoted.

The above listing is exemplary only and is not intended to limit thescope of the invention.

An additional embodiment of the invention includes methods andformulations that contain chemoprotectants and are administered byinhalation for preventing toxicity and particularly pulmonary toxicitythat may be elicited by antineoplastic drugs. The method would allow theuse by inhalation of antineoplastic drugs that exhibit pulmonarytoxicity or would reduce the likelihood of pulmonary toxicity. Onemethod would include treating a patient having a neoplasm, viainhalation administration, a pharmaceutically effective amount of ahighly toxic antineoplastic drug and a pharmaceutically effective amountof a chemoprotectant, wherein the chemoprotectant reduces or eliminatestoxic effects in the patient that are a result of inhaling the highlytoxic antineoplastic drug. More narrowly, another embodiment includes acombination of inhaled chemoprotectant and antineoplastic drug thatreduces or eliminates respiratory tract or pulmonary tract toxicity inthe patient. The chemoprotectant can be coadministered with theantineoplastic drug by inhalation, or both by inhalation and by IV, orthe chemoprotectant can be administered alone.

It is known, for example, that dexrazoxane (ICRF-187) when given byintraperitoneal injection to mice is protective against pulmonary damageinduced by bleomycin given by subcutaneous injections. See for exampleHerman, Eugene et al, “Morphologic and morphometric evaluation of theeffect of ICRF-187 on bleomycin-induced pulmonary toxicity”, Toxicology98, (1995) pp. 163-175, the text of which is incorporated by referenceas if fully rewritten herein. The mice pretreated with intraperitonealinjections of dexrazoxane prior to having bleomycin injectedsubcutaneously showed reduced pulmonary alterations particularlyfibrosis compared to another group of mice that was not pretreated.

The following examples illustrate the use of a chemoprotectant byinhalation in conjunction with an antineoplastic drug.

EXAMPLE 34

Dexrazoxane (ICRF-187) is dissolved in a pharmaceutically acceptableliquid formulation and administered to a patient as an aerosol using theapparatus and methods described herein, at a dose ranging from 10 mg to1000 mg over a period of from one minute to one day prior to giving achemotherapeutic drug such as doxorubicin by inhalation. The doxorubicinis given in a dose from 1 mg to 50 mg.

EXAMPLE 35

Dexrazoxane (ICRF-187) is administered as described in Example 34 at thesame time or up to two hours before giving bleomycin by intravenousinjection. The dose of dexrazoxane ranges form about 2 times to about 30times the dose of bleomycin. The dose of bleomycin by IV ranges fromabout 5 to 40 units/m².

EXAMPLE 36

Dexrazoxane (ICRF-187) is administered as described in Example 34 at thesame time or up to two hours before administering bleomycin byinhalation. The dose of dexrazoxane ranges from about 2 times to about30 times the dose of bleomycin. The dose of bleomycin by inhalationranges from 5 to 40 units/m² at intervals of from 1 week to 4 weeks.

EXAMPLES 37 and 38

Chemoprotectants such as mesna (ORG-2766), and ethiofos (WR2721) may beused in a manner similar to that described in Examples 34 to 36, above.

Combination Therapy

Another embodiment of the invention contemplates drug coadministrationby the pulmonary route, and by (1) other local routes, and/or (2)systemically by IV. Results from the clinical tests on dogs indicatesthat, although the pulmonary route of administration will indeed controlneoplastic cells arising in or metastatic to the pulmonary tract,neoplastic cells elsewhere in the body may continue to proliferate. Thisembodiment provides for effective doses of drug in the lung deliveredvia the lung and additional drug delivered via (1) other local sites(e.g. liver tumors may also be treated via hepatic artery instillation,ovarian cancer by intraperitoneal administration) and/or additionaldrug(s) may be provided systemically by IV via the general circulatorysystem. Administration can be at the same time, or administrationfollowed closely in time by one or more of the other therapeutic routes.Benefits are that much higher dosages can be supplied to affectedtissues and effective control of neoplasms can be maintained at multiplecritical sites compared to using a single mode of administration.

Also contemplated within the scope of the invention is the combinationof drugs for combination chemotherapy treatment. Benefits are those wellknown in the treatment of cancer using combination chemotherapy by otherroutes of administration. For example, combining drugs with differentmechanisms of action such as an alkylating agent plus a mitotic poisonplus a topoisomerase inhibitor. Such combinations increase thelikelihood of destroying tumors that are comprised of cells with manydifferent drug sensitivities. For example, some are easily killed byalkylating agents while mitotic poisons kill others more easily.

Also included in the invention are embodiments comprising the method forinhalation therapy disclosed herein and the application of radiotherapy,gene therapy, and/or immunotherapy. Other embodiments include theimmediately above method combined with chemotherapy applied by IV and/orlocal therapy.

Also included within the invention are formulations for paclitaxel. Inthese formulations 100% to 40% ethanol is useful. However, to obtainbetter control of particle size and stable aerosol generation theaddition of polyethylene glycol (PEG) is preferred. Although 1-60% PEGcan be used about 8-40% PEG is more preferred, and 10-30% PEG was foundto be optimal. A further embodiment also includes the addition of 0.01to 2% of an organic or inorganic acid, preferably an organic acid suchas citric acid and the like. The acid being added to stabilize theformulation. With regard to clinical use in inhalation, citric acid inwater has been found to cause tussive and bronchioconstrictive effects.PEG may ameliorate this effect. The formulation contains a safe andeffective amount of paclitaxel useful for the treatment of neoplasms.

While the forms of the invention herein disclosed constitute presentlypreferred embodiments, many others are possible. It is not intendedherein to mention all of the possible equivalent forms or ramificationsof the invention. It is to be understood that the terms used herein aremerely descriptive, rather than limiting, and that various changes maybe made without departing from the spirit of the scope of the invention.

We claim:
 1. A method of treating cancer of the respiratory tract in apatient in need of treatment which comprises administering by inhalationa pharmaceutically safe and effective amount of a vesicant anthracyclineanti-cancer agent, wherein said anti-cancer agent is unencapsulated. 2.A method according to claim 1 wherein said anthracycline anti-canceragent is selected from the group consisting of doxorubicin, epirubicin,daunorubicin, cyanomorpylinyldoxorubicin and idarubicin.
 3. A methodaccording to claim 2 wherein said anthracycline anti-cancer agent isselected from the group consisting of doxorubicin and epirubicin andidarubicin.
 4. A method according to claim 1 wherein said anthracyclineanti-cancer agent is doxorubicin.
 5. A method according to claim 1wherein said anthracycline anti-cancer agent is epirubicin.
 6. A methodaccording to claim 1 wherein said anthracycline anti-cancer agent isidarubicin.
 7. A method according to claim 1 wherein said anthracyclineanti-cancer agent is administered by inhalation as an aerosolizedliquid, powder or gas.
 8. A method according to claim 7 wherein saidaerosolized anthracycline is administered as an aerosolized liquid.
 9. Amethod according to claim 7 wherein said aerosolized anthracycline isadministered as an aerosolized powder.
 10. A method according to claim 7wherein said anthracycline is doxorubicin, epirubicin or idarubicin. 11.A method according to claim 7 wherein said anthracycline anti-canceragent is administered as an aerosolized liquid at a dosage of from about3 mg/m² body surface area to about 130 mg/m² body surface area.
 12. Amethod according to claim 7 wherein said anthracycline anti-cancer agentis administered as an aerosolized powder at a dosage of from about 3mg/m² body surface area to about 130 mg/m² body surface area.
 13. Amethod according to claim 1 wherein said anthracycline anti-cancer agentis administered at a dosage of from about 3 mg/m² body surface area toabout 130 mg/m² body surface area.
 14. A method according to claim 1wherein the particle size of said aerosol is from about 0.1 μm to about10.0 μm.
 15. A method according to claim 14 wherein the particle size ofsaid aerosol is from about 1.0 μm to about 5.0 μm.
 16. A methodaccording to claim 15 wherein the particle size of said aerosol is fromabout 2.0 μm to about 2.5 μm.
 17. A method according to claim 1 whereinone or more non-anthracycline vesicant anti-cancer agents areadministered by inhalation at the same time as the anthracyclineanticancer agent.
 18. A method of treating cancer of the respiratorytract in a patient which comprises administering to said patient apharmaceutically safe and effective amount of an aerosolized active drugsubstance which is an anthracycline anti-cancer agent; wherein saidanthracycline anti-cancer agent is administered at a dosage of fromabout 3 mg/m² body surface to about 130 mg/m² body surface area; whereinsaid active drug substance is delivered to said patient using a meansfor aerosolization of said active drug substance; and wherein theparticle size of said aerosolized drug substance is from about 0.1 μm.19. A method according to claim 18 wherein said anthracyclineanti-cancer agent is selected from the group consisting of doxorubicin,epirubicin, and idarubicin.
 20. A method according to claim 19 whereinsaid anthracycline anti-cancer agent is doxorubicin.
 21. A methodaccording to claim 19 wherein said anthracycline anti-cancer agent isepirubicin.
 22. A method according to either of claim 18 wherein saidanthracycline anti-cancer agent is administered as an aerosolized liquidor powder.
 23. A method according to claim 22 wherein said anthracyclineanti-cancer agent is doxorubicin or epirubicin and is administered as anaerosolized liquid.
 24. A method according to claim 22 wherein saidanthracycline anti-cancer agent is doxorubicin or epirubicin and isadministered as an aerosolized powder.